Glycopeptide antibiotic derivatives

ABSTRACT

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity aginst a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

This application is a division of application Ser. No. 08/356,413 filed Dec. 15, 1994, now abandoned, which is in turn a continuation-in-part of then copending application Ser. No. 08/189,393, filed Jan. 28, 1994, now abandoned.

BACKGROUND OF THE INVENTION

New improved antibiotics are continually in demand, particularly for the treatment of human diseases. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties are some of the goals for improved antibiotics.

In the search for new antibiotics, structural modification of known antibiotics is attempted whenever possible. The glycopeptide antibiotics have such complex structures that even small changes are difficult. Furthermore, it is difficult to predict the effect these changes will make in the antimicrobial and physiological properties. Processes for modifying known antibiotics and the new active derivatives made by such processes, Wherefore, continue to be of great importance.

Previously, N-alkyl and N-acyl derivatives of the glycopeptides vancomycin, A51568A, A51568B, M43A and M43D have been prepared (U.S. Pat. Nos. 4,639,433, 4,643,987, and 4,698,327). Several of these compounds exhibited microbiological activity, including activity against vancomycin-resistant isolates. Nicas et al., Antimicrobial Agents and Chemotherapy, 33(9):1477-1481 (1989). In addition, European Patent Application Publication No. 0435503, published Jul. 3, 1993, describes certain N-alkyl and N-acyl derivatives of the A82846 glycopeptides, factors A, B, and C.

The formula I compounds of this invention are new members of the glycopeptide group of antibiotics. These new compounds are derivatives of known glycopeptide antibiotics that include vancomycin (U.S. Pat. No. 3,067,099); A82846A, A82846B, and A82846C (U.S. Pat. No. 5,312,738, European Patent Publication 256,071 A1); PA-42867 factors A, C, and D (U.S. Pat. No. 4,946,941 and European Patent Publication 231,111 A2); A83850 (U.S. Pat. No. 5,187,082); avoparcin (U.S. Pat. No. 3,338,786 and U.S. Pat. No. 4,322,343); actinoidin, also known as K288 (J. Antibiotics Series A 14:141 (1961); helevecardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 86/157,397); galacardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 89/221,320); and M47767 (European Patent Publication 339,982). The references listed above which describe these glycopeptides are incorporated herein by reference.

Enterococci are important human pathogens. Infections caused by enterococci are generally difficult to treat. Glycopeptides, such as vancomycin and teicoplanin, have become important therapies in the treatment of infections due to enterococci. However, strains of Enterococcus faecium and E. faecalis have recently been isolated that are resistant to vancomycin and teicoplanin. Leclercq et al., "Plasmid Mediated Resistance to Vancomycin and Teicoplanin in Enterococcus Faecium," The New England Journal of Medicine, 319(3):157-161 (1988), and Uttley et al., "Vancomycin-Resistant Enterococci," Lancet, 1:57-58 (1988). The isolates were also found to be resistant to other antibiotics. A recent survey found 7.9% of Enterococci in United States hospitals are now vancomycin resistant. "Nosocomial Enterococci Resistant to Vancomycin" Morbidity and Mortality Weekly Resort 42 (30):597-598 (1993). In addition to their broad activity against gram-positive organisms, many of the glycopeptide compounds of this invention also exhibit improved antimicrobial activity against vancomycin-resistant isolates.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula I: ##STR1## or salt thereof, wherein:

X and Y are each independently hydrogen or chloro;

R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;

R¹ is hydrogen, or mannose;

R² is --NH₂, --NHCH₃, or--N(CH₃)₂ ;

R³ is --CH₂ CH(CH₃)₂, p-OH, m-Cl!phenyl, p-rhamnose-phenyl, or

p-rhamnose-galactose!phenyl, p-galactose-galactose!phenyl, p-CH₃ O-rhamnose!phenyl;

R⁴ is --CH₂ (CO)NH₂, benzyl, p-OH!phenyl, or p-OH, m-Cl!phenyl;

R⁵ is hydrogen, or mannose;

R⁶ is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, or L-actinosaminyl;

R⁷ is (C₂ -C₁₆)alkenyl, (C₂ -C₁₂)alkynyl, (C₂ -C₂ alkyl)-R₈, (C₁ -C₁₂ alkyl)-halo, (C₂ -C₆ alkynyl)-R₈, (C₂ C6 alkynyl)-R₈, (C₁ -C₁₂ alkyl)--O--R₈, and is attached to the amino group of R⁶ ;

R⁸ is selected from the group consisting of:

a) multicyclic aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) hydroxy,

(ii) halo,

(iii) nitro,

(iv) (C₁ -C₆)alkyl,

(v) (C₁ -C₆)alkenyl,

(vi) (C₁ -C₆)alkynyl,

(vii) (C₁ -C₆)alkoxy,

(viii) halo-(C₁ -C₆)alkyl,

(ix) halo-(C₁ -C₆)alkoxy,

(x) carbo-(C₁ -C₆)alkoxy,

(xi) carbobenzyloxy,

(xii) carbobenzyloxy substituted with (C₁ -C6)alkyl, (C₁ -C₆)alkoxy, halo, or nitro,

(xiii) a group of the formula --S(O)_(n') --R⁹, wherein n'is 0-2 and R⁹ is (C₁ -C₆)alkyl, phenyl, or phenyl substituted with (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, halo, or nitro, and

(xiv) a group of the formula --C(O)N(R¹⁰)₂ wherein each R¹⁰ substituent is independently hydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)- alkoxy, phenyl, or phenyl substituted with (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, halo, or nitro;

b) heteroaryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) halo,

(ii) (C.sub. -C₆)alkyl,

(iii) (C₁ -C₆)alkoxy,

(iv) halo-(C_(1-C) ₆)alkyl,

(v) halo-(C₁ -C₆)alkoxy,

(vi) phenyl,

(vii) thiophenyl,

(viii) phenyl substituted with halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkenyl, (C₁ -C₆)alkynyl, (C₁ -C₆)alkoxy, or nitro,

(ix) carbo-(C₁ -C₆)alkoxy,

(x) carbobenzyloxy,

(xi) carbobenzyloxy substituted with (C₁ -C₆)alkyl, (C₁ -C₆) alkoxy, halo, or nitro,

(xii) a group of the formula --S(O)_(n') --R⁹, as defined above,

(xiii) a group of the formula --C(O)N(R¹⁰)₂ as defined above, and

(xiv) thienyl;

c) a group of the formula: ##STR2##

wherein A¹ is --OC(A²)₂ --C(A²)₂ --O--, --O--,C(A²)₂ --O--,C(A²)₂ --O--, or -C(A²)₂ -C(A²)₂ -C(A²)₂ -C(A²)₂ -, and each A² substituent is independently selected from hydrogen, (C₁ -C6)-alkyl, (C₁ -C₆)alkoxy, and (C₄ 13 C₁₀)cycloalkyl;

d) a group of the formula: ##STR3##

wherein p is from 1 to 5; and

R¹¹ is independently selected from the group consisting of:

(i) hydrogen,

(ii) nitro,

(iii) hydroxy,

(iv) halo,

(v) (C₁ -C₈)alkyl,

(vi) (C₁ -C₈)alkoxy,

(vii) (C₉ -C₁₂)alkyl,

(viii)(C₂ -C₉)alkynyl,

(ix) (C₉ -C₁₂)alkoxy,

(x) (C₁ -C₃)alkoxy substituted with (C₁ -C₃)alkoxy, hydroxy, halo(C₁ 'C₃)aikoxy, or (C₁ -C₄)alkylthio,

(xi) (c₂ -C₅)alkenyloxy,

(xii) (C₁ -C₁₃)alkynyloxy

(xiii) halo-(C₁ -C6)alkyl,

(xiv) halo-(C₁ -C₆)alkoxy,

(xv) (C₂ -C₆)alkylthio,

(xvi) (C₂ -C₁₀)alkanoyloxy,

(xvii) carboxy-(C₂ -C₄)alkenyl,

(xviii) (C₁ -C₃)alkylsulfonyloxy,

(xix) carboxy-(C₁ -C₃)alkyl,

(xx) N- di(C₁ -C₃)-alkyl!amino-(C₁ -C₃)alkoxy,

(xxi) cyano-(C₁ -C₆)alkoxy, and

(xxii) diphenyl-(C₁ -C₆)alkyl,

with the proviso that when R¹¹ is (C₁ -C₈)alkyl, (C₁ -C₈)alkoxy, or halo, p must be greater or equal to 2, or when R⁷ is (C₁ -C₃ alkyl)-R⁸ then R¹¹ is not hydrogen, (C₁ -C₈)alkyl, (C₁ -C₈)alkoxy, or halo;

e) a group of the formula: ##STR4##

wherein q is 0 to 4;

R¹² is independently selected from the group consisting of:

(i) halo,

(ii) nitro,

(iii) (C_(1-C) ₆)alkyl,

(iv) (C₁ -C₆)alkoxy,

(v) halo-(C₁ -C₆)alkyl,

(vi) halo-(C₁ -C₆)alkoxy, and

(vii) hydroxy, and

(vii) (C₁ -C₆)thioalkyl;

r is 1 to 5; provided that the sum of q and r is no greater than 5;

Z is selected from the group consisting of:

(i) a single bond,

(ii) divalent (C₁₄ C₆)alkyl unsubstituted or substituted with hydroxy, (C_(1-C) 6)alkyl, or (C₁ -C₆)alkoxy,

(iii) divalent (C₂ -C₆)alkenyl,

(iv) divalent (C₂ -C₆)alkynyl, or

(v) a group of the formula --(C(R¹⁴)₂)s--R¹⁵ --or --R¹⁵ --(C(R¹⁴)₂)_(s) --, wherein s is 0-6; wherein each R¹⁴ substituent is independently selected from hydrogen, (C₁ -C₆)-alkyl, or (C₄ -C₁₀) cycloalkyl; and R¹⁵ is selected from --O--, --S--, --SO--, --SO₂ --, --SO₂ --O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C₁ -C₆ alkyl)-, and --C(O)NH--, --NHC(O)--, N═N;

R¹³ is independently selected from the group consisting of:

(i) (C₄ -C₁₀)heterocyclyl,

(ii) heteroaryl,

(iii) (C_(4-C) ₁₀)cycloalkyl unsubstituted or substituted with (C₁ -C₆)alkyl, or

(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C₁ -C₁₀) alkyl, (C₁ -C₃)alkoxy, halo-(C₁ -C₃)alkoxy, halo-(C₁ -C₃)alkyl, (C₁ -C₃)alkoxyphenyl, phenyl, phenyl-(C1-C₃)alkyl, (C₁ -C₆)alkoxyphenyl, phenyl-(C_(1-C) ₃)alkynyl, and (C₁ -C₆)alkylphenyl;

f) (C₄ -C¹⁰)cycloalkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) (C₁ -C₆)alkyl,

(ii) (C₁ -C6)alkoxy,

(iii) (C₁ -C₆)alkenyl,

(iv) (C₁ -C₆)alkynyl,

(v) (C₄ -C₁₀)cycloalkyl,

(vi) phenyl,

(vii) phenylthio,

(viii) phenyl substituted by nitro, halo, (C_(1-C) ₆)alkanoyloxy, or carbocycloalkoxy, and

(ix) a group represented by the formula --Z--R¹³ wherein Z and R¹³ are as defined above; and

g) a group of the formula: ##STR5##

wherein

A³ and A⁴ are each independently selected from

(i) a bond,

(ii) --O--,

(iii) --S(O)_(t) --, wherein t is 0 to 2,

(iv) --C(R¹⁷)₂ --, wherein each R¹⁷ substituent is independently selected from hydrogen, (C₁ -C₆)alkyl, hydroxy, (C_(l) -C₆)alkyl, (C₁ -C₆)alkoxy, or both R¹⁷ substituents taken together are O,

(v) --N(R¹⁸)₂ --, wherein each R¹⁸ substituent is independently selected from hydrogen; (C₁ -C₆)alkyl; (C₁ -C₆)alkenyl; (C₁ -C₆)alkynyl; (C₄ -C₁₀)cycloalkyl; phenyl; phenyl substituted by nitro, halo, (C₁ -C₆)alkanoyloxy; or both R¹⁸ substituents taken together are (C₄ -C₁₀)cycloalkyl;

R¹⁶ is R¹² or R¹³ as defined above; and

u is 0-4.

Another aspect of the invention relates to compositions for the treatment of susceptible bacterial infections comprising a compound of formula I in combination with an acceptable pharmaceutical carrier. Methods for the treatment of susceptible bacterial infections with compositions of formula I are also a part of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The alkyl substituents recited herein denote substituted or unsubstituted, straight or branched chain hydrocarbons of the length specified. The term "alkenyl" refers to a substituted or unsubstituted, straight or branched alkenyl chain of the length specified. The term "alkynyl", refers to a substituted or unsubstituted, straight or branched alkynyl chain of the length specified.

The alkoxy substituents recited herein represent an alkyl group attached through an oxygen bridge. The term "alkenoxy" represents a alkenyl chain of the specified length attached to an oxygen atom.

The term "multicyclic aryl" means a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring; a stable, saturated or unsaturated, substituted or unsubstituted 12 to 14 membered organic fused tricyclic ring; or a stable, saturated or unsaturated, substituted or unsubstituted 14 to 16 membered organic fused tetracyclic ring. The bicyclic ring may have 0 to 4 substituents, the tricyclic ring may have 0 to 6 substituents, and the tetracyclic ring may have 0 to 8 substituents. Typical multi-cyclic aryls include fluorenyl, napthyl, anthranyl, phenanthranyl, biphenylene and pyrenyl.

The term "heteroaryl" represents a stable, saturated or unsaturated, substituted or unsubstituted, 4 to 7 membered organic monocyclic ring having a hetero atom selected from S, O, and N; a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring having 1 to 2 hetero atoms selected from S, O, and N; or a stable, saturated or unsaturated, substituted or unsubstituted, 12 to 14 membered organic fused tricyclic ring having a hetero atom selected from S, O, and N. The nitrogen and sulfur atoms of these rings are optionally oxidized, and the nitrogen hetero atoms are optionally quarternized. The monocyclic ring may have 0 to 5 substituents. The bicyclic ring may have 0 to 7 substituents, and the tricyclic ring may have 0 to 9 substituents. Typical heteroaryls include quinolyl, piperidyl, thienyl, piperonyl, oxafluorenyl, pyridyl and benzothienyl and the like.

The term "(C₄ -C₁₀)cycloalkyl" embraces substituents having from four to ten carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl which may be unsubstituted or substituted with substituents such as alkyl and phenyl. This term also embraces C₅ to C₁₀ cycloalkenyl groups such as cyclopentenyl and cyclohexenyl. The term " (C₄ -C₁₀)cycloalkyl" also embraces bicyclic and tricyclic cycloalkyls such as bicyclopentyl, bicylohexyl, bicycloheptyl, and adamantyl.

The term "alkanoyloxy" represents an alkanoyl group attached through an oxygen bridge. These substituents may be substituted or unsubstituted, straight, or branched chains of the specified length.

The term "cyano-(C₁ -C₆)alkoxy" represents a substituted or unsubstituted, straight or branched alkoxy chain having from one to six carbon atoms with a cyano moiety attached to it.

The term "divalent (C₁ -C₆)alkyl" represents an unsubstituted or substituted, straight or branched divalent alkyl chain having from one to six carbon atoms. Typical divalent (C₁ -C₆)alkyl groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, neo-pentylene, and hexylene. Such divalent (C₁ -C₆)alkyl groups may be substituted with substituents such as alkyl, alkoxy, and hydroxy.

The term "divalent (C₂ -C6)alkenyl" represents a straight or branched divalent alkenyl chain having from two to six carbon atoms. Typical divalent (C₂ -C₆)alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and the like.

The term "divalent (C₂ -C₆)alkynyl" represents a straight or branched divalent alkynyl chain having from two to six carbon atoms. Typical divalent (C₂ C₆)alkynyl include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene and the like.

The term "halo" represents chloro, fluoro, bromo or iodo.

The term "halo-(C₁ -C₆)alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C₁ -C₆)alkyl groups include chloromethyl, 2-bromoethyl, 1- -chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3- chloroisobutyl, iodo-t-butyl, trifluoromethyl, and the like.

The term "halo-(C₁ -C₆)alkoxy" represents a straight or branched alkoxy chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C₁ -C₆)alkoxy groups include chloromethoxy, 2-bromoethoxy, 1-chloroisopropoxy, 3-fluoropropoxy, 2,3-dibromobutoxy, 3- chloroisobutoxy, iodo-t-butoxy, trifluoromethoxy, and the like.

The term "heterocyclyl" embraces saturated groups having three to ten ring members and which heterocyclic ring contains a hetero atom selected from oxygen, sulfur and nitrogen, examples of which are piperazinyl, morpholino, piperdyl, methylpiperdyl, azetidinyl, and aziridinyl.

The invention includes salts of the compounds defined by formula I. Although generally neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l- sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, acetic acid, and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. The compounds of the present invention are prepared from compounds of the formula: ##STR6##

The compounds of formula II are defined in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     Formula II Compounds.sup.a                                                     antibiotic                                                                           R  R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                             R.sup.4                                                                               R.sup.5                                                                               R.sup.6                                                                           X Y                                       __________________________________________________________________________     vancomycin                                                                           H  van                                                                               H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A82846A                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H Cl                                      A82846B                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A82846C                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H H                                       PA-42867-A                                                                           4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               H                                       PA-42867-C                                                                           4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H H                                       PA-42867-D                                                                           4-epi                                                                             4-epi                                                                             H  N(CH.sub.3).sub.2                                                                   CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               H                                       A83850A                                                                              H  keto                                                                              H  N(CH.sub.3).sub.2                                                                   CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A83850B                                                                              H  keto                                                                              H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      actinoidin                                                                           actin                                                                             acos                                                                              H  NH.sub.2                                                                            p-OH,m-Cl-                                                                            benzyl man                                                                               Cl                                                                               H                                                           phenyl                                                     avoparcin                                                                            risto                                                                             risto                                                                             man                                                                               N(CH.sub.3).sub.2                                                                   p-rha- p-OH-  H  H H                                                           phenyl phenyl                                              galacardin                                                                           risto                                                                             risto                                                                             man                                                                               NHCH.sub.3                                                                          p-gal--gal-                                                                           p-OH-  H  Cl                                                                               H                                                           phenyl phenyl                                              heleve-                                                                              risto                                                                             risto                                                                             H  NHCH.sub.3                                                                          p-CH.sub.3 O--rha-                                                                    p-OH,m-Cl-                                                                            H  Cl                                                                               H                                       cardin      or      phenyl phenyl                                                          man                                                                M47767                                                                               actin                                                                             acos                                                                              H  NHCH.sub.3                                                                          p-OH,m-Cl-                                                                            benzyl man                                                                               Cl                                                                               H                                                           phenyl                                                     __________________________________________________________________________      .sup.a Abbreviations for the formula II compounds are: actin =                 actinosaminyl; acos = acosaminyl; 4epi = 4epi-vancosaminyl; gal =              galactosyl; keto = 4keto-vancosaminyl; man = mannose; rha = rhamnosyl;         rha--gal = rhamnosylgalactosyl; risto = ristosaminyl; van = vancosaminyl.

In a preferred embodiment of the invention, the formula I compounds are prepared from the A82846 antibiotics (A82846A, A82846B, and A82846C) and PA-42867-A. In a more preferred embodiment, the compounds of the present invention are prepared from A82846B ("A82846B derivatives"). A82846B is represented by formula I compounds wherein R is 4-epi-vancosaminyl, R¹ is hydrogen, R² is NHCH₃, R³ is CH₂ CH(CH₃)₂, R⁴ is CH₂ (CO)NH₂, R⁵ is hydrogen, R⁶ is 4-epi-vancosaminyl and X and Y are Cl. A82846B derivatives of the present invention having substituents at position R⁷ of formula I are list herein in the manner "R⁷ - A82846B". For example, the compound "phenylbenzyl-A82846B" has a phenylbenzyl substituent at position R⁷ in formula I.

Preferred formula I compounds include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R₈ is an unsubstituted multicyclic aryl. of this group, naphthylmethyl-A82846B, acenapthlenyl-methyl-A82846B, and fluorenylmethyl-A82846B are more preferred.

Preferred formula I compounds also include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is an unsubstituted heteroaryl or a heteroaryl substituted by halophenyl. Of this group, 1-oxa!fluorenylmethyl-A82846B, chlorophenylbenzoxazolemethyl-A82846B, and phenylthienylmethyl-A82846B are more preferred.

Further preferred compounds of formula I include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is a group of the formula: ##STR7## wherein p is 1 and R¹¹ is selected from (C₂ -C₅)alkenyloxy, halo-(C₁ -C₆)alkoxy, (C₂ -C₁₀)alkanoyloxy, (C₁ -C₃)alkoxy substituted with (C₁ -C₄)alkylthio, and diphenyl-(C₁ -C₆)alkyl. Of this group, trifluromethoxybenzyl-A82846B, diphenylmethylbenzyl- A82846B, thiopropylethoxybenzyl-A82846B, acetoxybenzyl-A82846B, nonanoyloxybenzyl-A82846B, and tetrafluoroethoxybenzyl-A82846B are more preferred.

Still further preferred compounds of formula I include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is a group of the formula: ##STR8##

wherein q is 1 to 5; r is 1; Z is selected from a single bond, divalent (C₁ -C₆)alkyl, divalent (C₂ -C6)alkenyl, and --R¹⁵ --(C(R¹⁴)2)s--, wherein R¹⁵ is selected from --O--, --S--, --SO₂ --, and --OC(O)--, each R¹⁴ substituent is hydrogen, and s is 0 or 1; and R¹³ is selected from: (C₄ -C₁ O)cycloalkyl; phenyl; and phenyl substituted by nitro, halo, (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy, or halo(C₁ -C₃)alkyl. Of this group, chlorophenylbenzyl-A82846B, phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl- A82846B, A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-A82846B, fluorophenylbenzyl-A82846B, phenylethynylbenzyl-A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A82846B, nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B, chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B, trifluoromethylphenoxybenzyl-A82846B, dichlorophenoxybenzyl- A82846B, nitrobenzyloxybenzyl-A82846B, benzoyloxybenzyl-A82846B, cyclohexyloxybenzyl-A82846B, cyclohexanoyloxybenzyl-A82846B, thiophenylbenzyl-A82846B, chlorophenylsulfonylbenzyl-A82846B, and cyclohexylbenzyl-A82846B, cyclohexylethoxybenzyl-A82846B, chlorophenoxynitro-benzyl-A82846B benzylmethoxybenzyl-A82846B, chlorophenoxynitro-benzyl-A82846B, and phenoxymethoxybenzyl-A82846B, benzoyloxy-dimethoxybenzyl-A82846B, cyclohexanoyloxy-dimethylbenzyl-A82846B, trifluoromethylphenylbenzyl-A82846B, butylphenylthiobenzyl-A82846B, and bromophenylbenzyl-A82846B more preferred.

Still further preferred compounds of formula I include A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is (C₄ -C₁₀)cycloalkyl substituted with (C₄ -₁₀)cycloalkyl. Of this group of compounds, more preferred is cyclohexyl-cyclohexylmethyl-A82846B and butyl-cyclohexylmethyl-A82846B.

Formula I compounds that are prepared from A83850A or A83850B can be prepared from the reduced forms of these compounds. The reduced forms of compounds A83850A or A83850B are produced according to the method described in U.S. Pat. No. 5,187,082, which is incorporated herein by reference.

The compounds of this invention are prepared by reacting a formula II compound with an aldehyde to form an intermediate Schiff's base, which is subsequently reduced with a metal borohydride to give the desired N-alkyl amine.

In the first method of making the compounds of this invention, hereinafter Method A (described in Examples 1 and 2), the reaction for the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in a polar solvent, such as dimethylformamide (DMF) or methanol (MeOH), or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25° C. to about 100° C. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. for 30 minutes to 2 hours in a mixture of dimethylformamide and methanol, or in methanol. The intermediate Schiff's base is then reduced, preferably without isolation, to produce the corresponding N-alkyl derivative(s). The reduction of the Schiff's base can be effected using a chemical reducing agent such as a metal borohydride, for example, sodium borohydride or sodium cyanoborohydride. The reduction reaction can be carried out in a polar organic solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol. The reduction reaction can be carried out at a temperature of about 25° C. to about 100°C. for 1 to 5 hours. The reduction reaction is preferably carried out using an excess of sodium cyanoborohydride in a mixture of dimethylformamide and methanol or in methanol at about 60° C. to about 70° C for 1 to 2 hours. Method A is preferable for benzylic aldehydes.

In a second method of making compounds of this invention, hereinafter Method B (described in Example 3), the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in the presence of the reducing agent, sodium cyanoborohydride, in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25° C. to about 100° C for 1 to 5 hours. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. for 1 to 2 hours in a mixture of dimethylformamide and methanol. Method B is preferable for non- benzylic aldehydes.

In a third method of making compounds of this invention, hereinafter Method C (described in Example 4), the formation of the Schiff's base is carried out a) under an inert atmosphere, such as nitrogen or argon, b) in the presence of the reducing agent, such as a metal borohydride, with sodium cyanoborohydride being most preferred, or a homogenous or heterogeneous catalytic hydrogenation agent(s), such as Crabtree's catalyst, Wilkinson's catalyst, palladium on carbon, platinum on carbon, or rhodium on carbon, c) in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, and d) at a temperature of about 25° C. to about 100° C. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. in methanol. The reaction is allowed to continue for about 20 to about 28 hours, at which time the reaction mixture is adjusted to about pH 7.5 to about pH 10, with a pH of about 9.0 being preferred. The pH adjustment halts the reaction. Because the product is marginally soluble in polar solvents, the solvent of the reaction can be exchanged to an alcohol such as ethanol, butanol, or isopropanol, with isopropanol being preferred, to allow for precipitation of the product. Method C is a preferred method of this invention in view of the increased product yield provided by this method. Another advantage of this reaction scheme is the increased ratio of preferred product (products substituted at the amino group of the sugar denoted as R¹ in Formula II compounds) to other products (products that are substituted at the amino groups of substitutents denoted as R and/or R³ of the Formula II compounds). By allowing the reaction to proceed for an extended period of time, such as 20 to 28 hours, products that are monosubstituted at positions denoted as R and R³ in the Formula II compounds are converted to disubstituted forms, making the preferred monosubstituted derivative easier to isolate.

The products of the reaction, obtained from either Method A, B, or C can be purified by preparative reverse phase HPLC utilizing Waters C13 Nova-Pak columns with ultraviolet light (UV; 235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minutes to 20% aqueous buffer/80% CH₃ CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

HPLC analysis of the reaction mixtures and final purified products can be accomplished utilizing a Waters C18 MicroBonda-Pak column (typically 3.9×300 mm steel) or Waters Nova-pak C18 RCM column (8×100 mm) with UV (235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minute to 20% aqueous buffer/80% CH₃ CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

The ratio of the aldehyde to the formula II compound and the reaction conditions determines the products of the reaction. The monosubstituted derivatives are those derivatives where a hydrogen atom of the amino group at position R¹ in formula II is replaced by one of the substituents listed above for formula I. When using Methods A or B, described above, the formation of monosubstituted derivatives substituted at the amino group of the amino sugar at position R¹ in the formula II compounds is favored by using a slight excess of aldehyde, a shorter reaction time, and a lower temperature. As noted above, Method C favors the formation of the monosubstituted derivative. The monosubstituted derivative is preferred. A large excess of the aldehyde favors the formation of disubstituted and trisubstituted derivatives of the formula II compounds. The disubstituted derivatives are the derivatives where a hydrogen atom at two of the locations selected from the amino .group at position R³ and the amino group of the amino sugars designated as R or R¹ in formula II, are replaced by the reduced aldehyde moiety. The trisubstituted derivatives are the derivatives where a hydrogen atom at three of the locations selected from the amino group at position R³, and the amino group of the amino sugars designated as R or R¹ in formula II, are replaced by the reduced aldehyde moiety.

Examples of compounds that have been prepared and are illustrative of the formula I compounds are listed in Tables 2A and 2B. Table 2A lists compounds prepared by reacting an aldehyde with the glycopeptide A82846B. Table 2A lists the sidechain substitutions on the amino group of the 4-epi-vancosaminyl sugar of the 4-epi-vancosaminyl-O-glycosyl disaccharide of the A82846B compound. All of the compounds listed are monosubstituted derivatives.

Table 2B lists those compounds that were prepared by reacting an aldehyde with a variety of glycopeptide antibiotics other than A82846B. The compounds of Table 2B are monosubstituted at the amino group of the amino sugar designated as R¹ in formula II with the sidechain listed. All of the compounds listed are monosubstituted derivatives.

                  TABLE 2A                                                         ______________________________________                                         COMPOUND NO.                                                                              SIDECHAIN                                                           ______________________________________                                         1          2-naphthylmethyl                                                    2          4-phenylbenzyl                                                      3          1-naphthylmethyl                                                    4          4-phenoxybenzyl                                                     5          4-benzyloxybenzyl                                                   6          4-trifluoromethoxybenzyl                                            7          4-allyloxybenzyl                                                    8          4-nonyloxybenzyl                                                    9          2-methoxy-1-naphthylmethyl                                          10         4-dodecyloxybenzyl                                                  11         9-phenanthranylmethyl                                               12         4-decyloxybenzyl                                                    13         9-anthranylmethyl                                                   14         4- phenylethynyl!4-phenylbenzyl                                     15         4-methoxy-1-naphthylmethyl                                          16         1-pyrenylmethyl                                                     17         9- 10-methyl!anthranylmethyl                                        18         9- 10-chloro!anthranylmethyl                                        19         2-benzthienylmethyl                                                 20         4- 4-hydroxyphenyl!benzyl                                           21         4- 4-octylphenyl!benzyl                                             22         4- 4-pentylphenyl!benzyl                                            23         4- 4-octyloxyphenyl!benzyl                                          24         3-pyridylmethyl                                                     25         5-nitro-1-naphthylmethyl                                            26         4-pyridylmethyl                                                     27         4-quinolylmethyl                                                    28         3-quinolylmethyl                                                    29         4-stilbenzyl                                                        30         2-quinolylmethyl                                                    31         2-pyridylmethyl                                                     32         2-fluorenylmethyl                                                   33         4-phenoxyphenethyl                                                  34         4- 4-pentylcyclohexyl!benzyl                                        35         4 -benzylphenethyl                                                  36         4- 4-biphenyl!benzyl                                                37         4-trifluoromethylbenzyl                                             38         trans-cinnamyl                                                      39         4- 1-oxa!fluorenylmethyl                                            40         4- 4-pentoxyphenyl!benzyl                                           41         4-thiomethylbenzyl                                                  42         2,3- 2-methyl-3- 4-t-butylphenyl!!propenyl                          43         9-(1-methyl)-acridinylmethyl                                        44         2-hydroxy-1-naphthylmethyl                                          45         4- 2-phenyl-6-methoxy!quinoylmethyl                                 46         4-diphenylmethylbenzyl                                              47         3,4 cyclohexenylmethyl                                              48         3,4-methylenedioxylbenzyl                                           49         3-phenoxybenzyl                                                     50         4-benzylbenzyl                                                      51         3-benzyloxy-6-methoxy benzyl                                        52         4-benzyloxy-3-methoxybenzyl                                         53         3,4-dibenzyloxybenzyl                                               54         4- 4-methoxyphenyl!benzyl                                           55         4- 3-cyanopropoxy!benzyl                                            56         3,4-ethylenedioxybenzyl                                             57         4- 4-nitrophenoxy!benzyl                                            58         2,3-methylenedioxybenzyl                                            59         2-benzyloxyphenethyl                                                60         2-ethoxy-1-naphthylmethyl                                           61         2-benzylfurylmethyl                                                 62         3-phenoxyphenethyl                                                  63         4-phenoxyphenethyl                                                  64         4- 4-nitrophenyl!benzyl                                             65         6-methoxy-2-naphthylmethyl                                          66         3-methyl-5-thienylmethyl                                            67         5-phenyl-2-thienylmethyl                                            68         4-benzyloxyphenethyl                                                69         3-benzyloxyphenethyl                                                70         4- 2-nitrophenoxy!benzyl                                            71         5- 4-methoxyphenyl!-2-thienylinethyl                                72         4-difluormethoxybenzyl                                              73         2,3,4,5,6-pentamethylbenzyl                                         74         5-iodo-2-thienylmethyl                                              75         4- 2- 2-chloroethoxy!ethoxy!benzyl                                  76         3,4-dimethylbenzyl                                                  77         3-acetoxybenzyl                                                     78         4-nitrobenzyl                                                       79         4-phenylethynylbenzyl                                               80         4- 2-chloro-6-fluorobenzyloxy!benzyl                                81         4- 3,4-dichlorophenoxy!benzyl                                       82         S- 2,3-dihydrobenzfuryl!methyl                                      83         4- 2- N,N-diethylamino!ethoxy!benzyl                                84         2-bicyclo 2.1.2!heptylmethyl                                        85         2-hydroxy-5-phenylbenzyl                                            86         3- 4-chlorophenoxy!benzyl                                           87         4- 3-chlorophenoxy!-3-nitrobenzyl                                   88         4- 2-chlorophenoxy!-3-nitrobenzyl                                   89         3,5-dimethylbenzyl                                                  90         4- 4-ethylphenyl!benzyl                                             91         3-phenylbenzyl                                                      92         4- 3-fluorophenyl!benzyl                                            93         4- 4-chlorobenzyloxy!benzyl                                         94         4- 4-chlorophenoxy!-3-nitrobenzyl                                   95         4- 4-methylphenoxy!benzyl                                           96         4- 4-t-butylphenoxy!benzyl                                          97         4- 4-methylphenyl!benzyl                                            98         4- 4-methoxyphenoxy!benzyl                                          99         4-acetoxy-3-methoxybenzyl                                           100        4- (2-phenyl)ethyl!benzyl                                           101        3- 5-phenyl!pyridinylmethyl                                         102        4- 2-nitrophenyl!benzyl                                             103        2- 1-hydroxy!fluorenylmethyl                                        104        4-benzyl-3-methoxybenzyl                                            105        4- cyclohexylmethoxy!-3-ethoxybenzyl                                106        3- 3,3'-dichlorophenoxy!benzyl                                      107        4- 4-propylphenyl!benzyl                                            108        4-thiophenylbenzyl                                                  109        4- alpha-hydroxybenzyl!benzyl                                       110        2,2-dinitro-4-thiophenebenzyl                                       111        3- 3-trifluoromethylphenoxy!benzyl                                  112        4- t-butylethynyl!benzyl                                            113        4-phenoxy-3-methoxy-benzyl                                          114        4- 3-trifluoromethylphenoxy!-3-nitrobenzyl                          115        2-phenylthiobenzyl                                                  116        2- 4-chlorophenyl!-6-benzoxazolemethyl                              117        4- alpha-methoxybenzyl!benzyl                                       118        4-cyclohexylbenzyl                                                  119        3- 3,4-dichlorophenoxy!benzyl                                       120        acenaphthlenylmethyl                                                121        4- 1,1,2,2-tetrafluoroethoxy!benzyl                                 122        4-benzoyloxy-3,3-dimethoxybenzyl                                    123        3- cyclohexylmethoxy!benzyl                                         124        4-cyclohexyloxybenzyl                                               125        3- 2-quinoylmethoxy!benzyl                                          126        4- alpha-ethoxybenzyl!benzyl                                        127        4- cyclohexylethoxy!benzyl                                          128        4- alpha-propoxybenzyl!benzyl                                       129        4- 4-methyl-1-piperidino!benzyl                                     130        2-thiophene-1,2-cyclohexenylmethyl                                  131        4- 4-nitrobenzyloxy!benzyl                                          132        3- 4-trifluoromethylphenoxy!benzyl                                  133        3-benzoyl-2,4-dichlorobenzyl                                        134        4- 2- 2-thiopropyl!ethoxy!benzyl                                    135        4- 2-methyl-1-piperidino!benzyl                                     136        4-hydroxybenzyl                                                     137        4- 2-pyridyl!benzyl                                                 138        4-acetoxybenzyl                                                     139        5,6-benzonorbornylmethyl                                            140        3-phenylcyclopentylmethyl                                           141        1-adamantylmethyl                                                   142        3- cyclohexylmethoxy!-4-methoxybenzyl                               143        2- 2-glucosyl!benzyl                                                144        4- 4-pentoxybiphenyl!benzyl                                         145        3,4-dihydroxybenzyl                                                 146        4- 4-methylpiperazino!benzyl                                        147        4-morpholinobenzyl                                                  148        4- 4-chlorophenylsulfonyl!benzyl                                    149        4-methylsulfonyloxybenzyl                                           150        4-benzoyloxybenzyl                                                  151        5-phenyl-3-pyridinylmethyl                                          152        4- N,N-bis(2-chloroethyl)amino!benzyl                               153        3-cyclohexyloxybenzyl                                               154        4- 2-t-butoxyethoxy!benzyl                                          155        3,3-dichloro-4-hydroxy-benzyl                                       156        1,2,3,4,-tetrahydro-9-anthranylmethyl                               157        4-cyclohexanoyloxybenzyl                                            158        4-nonanoyloxybenzyl                                                 159        4- phenylsulfinyl!benzyl                                            160        4-anilinobenzyl                                                     161        cyclohexylmethyl                                                    162        3-benzoyloxybenzyl                                                  163        3-nonanoyloxybenzyl                                                 164        4- cyclohexyl!cyclohexylmethyl                                      165        3-cyclohexanoyloxybenzyl                                            166        4- cyclohexanoyloxy!-3,3- dimethoxy!benzyl                          167        4- nonanoyloxy!-3,3- dimethoxy!benzyl                               168        1,2,3,4-tetrahydro-6-naphthylmethyl                                 169        2-hydroxybenzyl                                                     170         2- 6,6-dimethyl-bicyclo 3.1.1!hept-2-enyl!methyl                   171        1-cyclohexenyl-4-isopropylmethyl                                    172        4- 4-methoxyphenyl!butyl                                            173        4-  2,3,4,5,6-pentamethyl!phenylsulfonyloxy!benzyl                  174        4- 1-pyrrolidinosulfonyl!benzyl                                     175        3- 4-methoxyphenyl!propyl                                           176        8-phenyloctyl                                                       177        4- 2,3-dihydroxypropoxy!benzyl                                      178        4- N-methylanilino!benzyl                                           179        2- 2-napthyl!ethyl                                                  189        6-methyl-2-naphthylmethyl                                           190        cis-bicyclo 3.3.0!octane-2-methyl                                   191        2-tridecynyl                                                        192        4-butyl-2-cyclohexylmethyl                                          193        4- (4-fluorobenzoyl)amino!benzyl                                    194        4- (3-fluorobenzoyl)amino!benzyl                                    195        8-phenoxyoctyl                                                      196        6-phenylhexyl                                                       197        10-phenyldecyl                                                      198        8-bromooctyl                                                        199        11-tridecynyl                                                       200        8- 4-methoxyphenoxy!octyl                                           201        8- 4-phenylphenoxy!octyl                                            202        8- 4-phenoxyphenoxy!octyl                                           203        3- 3-trifluoromethylphenoxy!benzyl                                  204        10-undecenyl                                                        205        4-cyclohexylbutyl                                                   206        4-phenyl-2-fluorobenzyl                                             207        7-hexadecynyl                                                       208        3- cyclopentyl!propyl                                               209        4- 2-methylphenyl!benzyl                                            210        4- phenylazo!benzyl                                                 211        4- 4-flurophenyl!benzyl                                             212        3-nitro-4- 4-nitrophenyl!benzyl                                     213        3-nitro-4- 2-nitrophenyl!benzyl                                     214        9-decenyl                                                           215        4- 3,4-dimethoxyphenyl!benzyl                                       216        4- 4-trifluromethylphenyl!benzyl                                    217        5-hexenyl                                                           218        4- 2-thienyl!benzyl                                                 219        4- 6-phenylhexyloxy!benzyl                                          220        9,10-dihydro-2-phenantrene methyl                                   221        4- 3,4-dimethylphenyl!benzyl                                        222        4- 4-methylphenyl!-2-methylbenzyl                                   223        4- 3-phenylpropyloxy!benzyl                                         224        4- 3-methylphenyl!benzyl                                            225        4- 4-methylphenyl!-3-methylbenzyl                                   226        4- 4-pentenyloxy!benzyl                                             227        4- 1-heptynyl!benzyl                                                228        3- 4-t-butyl-phenylthio!benzyl                                      229        4- 4-chlorophenyl!benzyl                                            230        4- 4-bromophenyl!benzyl                                             231        4- 4-cyanophenyl!benzyl                                             232        4- 1-nonynyl!benzyl                                                 233        4- 11-tridecynyloxy!benzyl                                          234        12-phenyldodecyl                                                    235        6-phenyl-5-hexynyl                                                  236        11-phenyl-10-undecynyl                                              237        4- 2-methylphenyl!-3-methylbenzyl                                   238        3- 2-thienyl!-2-thienylmethyl                                       239        4- benzyloxymethyl!cyclohexylmethyl                                 240        4- 4-chlorophenoxy!benzyl                                           241        4- benzyl!cyclohexylmethyl                                          242        4-benzoylbenzyl                                                     243        4- phenoxymethyl!benzyl                                             244        4- 4-chlorobenzyl!benzyl                                            ______________________________________                                    

                  TABLE 2B                                                         ______________________________________                                         COMPOUND     GLYCOPEPTIDE                                                      NO.          CORE          SIDECHAIN                                           ______________________________________                                         180          vancomycin    1-napthylmethyl                                     181          vancomycin    4-phenylbenzyl                                      182          A82846A       4-phenylbenzyl                                      183          A82846C       4-phenylbenzyl                                      184          A82846C       4-phenoxybenzyl                                     185          PA-42867 A    4-phenylbenzyl                                      186          reduced A838450A                                                                             4-phenylbenzyl                                      187          alpha-avoparcin                                                                              4-phenylbenzyl                                      188          beta-avoparcin                                                                               4-phenylbenzyl                                      ______________________________________                                    

The formula I compounds have in vitro and in vivo activity against Gram-positive pathogenic bacteria. The minimal inhibitory concentrations (MIC) at which the formula I compounds inhibit certain bacteria are given in Table 3. The MIC's were determined using a standard broth micro-dilution assay.

                                      TABLE 3                                      __________________________________________________________________________     In Vitro Activity of Formula I Compounds                                       MIC (mcg/ml)/Compound                                                          __________________________________________________________________________     Organism       vancomycin                                                                           A82846A                                                                             A82846B                                                                             A82846C                                                                             1    2   3    4   5    6                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5   0.25 0.25 0.5  ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1    0.5                 Staphylococcus aureus 489                                                                     0.125 0.5  ≦.06                                                                         ≦.06                                                                         ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.5  0.25                Staphylococcus aureus 447                                                                     0.5   0.25 0.25 0.5  ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.5  0.5                 Staphylococcus aureus X400                                                                    0.5   0.125                                                                               0.125                                                                               0.25 ≦0.06                                                                        1   ≦0.06                                                                        ≦0.06                                                                       1    1                   Staphylococcus aureus X778                                                                    0.5   0.125                                                                               0.125                                                                               0.5  0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5  0.25                Staphylococcus aureus 491                                                                     1     0.25 0.25 1    2    ≦0.06                                                                       0.5  ≦0.06                                                                       0.5  0.125               Staphylococcus aureus S13E                                                                    0.5   0.125                                                                               0.125                                                                               0.25 0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1    0.25                Staphylococcus aureus SA1199                                                                  0.5   0.125                                                                               0.125                                                                               0.25 ≦0.06                                                                        0.5 0.125                                                                               ≦0.06                                                                       1    0.25                Staphylococcus aureus SA1199A                                                                 0.125 ≦.06                                                                         ≦.06                                                                         0.125                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        Staphylococcus aureus SA1199B                                                                 0.5   ≦.06                                                                         0.125                                                                               ≦.06                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06             Staphylococcus haemolyticus 105                                                               16    0.5  1    1    4    2   4    0.5 2    0.5                 Staphylococcus haemolyticus 415                                                               8     1    4    2    4    1   8    0.5 1    0.5                 Staphylococcus epidermidis 270                                                                16    0.25 0.25 0.125                                                                               8    8   8    ≦0.06                                                                       0.25 0.125               Entercoccus faecium 180                                                                       >64   16   8    16   0.5  0.25                                                                               0.5  0.125                                                                              ≦0.06                                                                        0.125               Entercoccus faecium 180-1                                                                     0.5   0.125                                                                               0.125                                                                               0.125                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        Entercoccus faecalis 2041                                                                     2     0.125                                                                               0.25 0.5  0.125                                                                               0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        Entercoccus faecalis 276                                                                      1     0.125                                                                               0.125                                                                               0.5  ≦0.06                                                                        0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06             Entercoccus gallinarum 245                                                                    4     0.125                                                                               0.25 0.5  4    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        Haemophilus influenzae RD                                                                     >64   >64  >64  >64  >64                    >64                 Escherichia coli EC14                                                                         >64   >64  >64  >64  >64  >64 >64  >64 >64  >64                 Streptococcus pyogenes C203                                                                   0.5             0.125                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        Streptococcus pneumoniae P1                                                                   0.25            ≦.06                                                                         ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06        __________________________________________________________________________     Organism       7   8   9   10   11  12   13  14   15  16  17                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     8   2   2   16   4   32   2   4    1   4   2                    Staphylococcus aureus 489                                                                     2   4   0.5 >64  1   8    1   2    ≦0.06                                                                       0.5 1                    Staphylococcus aureus 447                                                                     4   8   4   >64  4   32   8   8    2   4   8                    Staphylococcus aureus X400                                                                    1   8   0.5 >64  0.5 8    1   4    0.25                                                                               0.5 0.5                  Staphylococcus aureus X778                                                                    0.25                                                                               8   0.25                                                                               16   0.25                                                                               8    2   4    0.25                                                                               2   0.5                  Staphylococcus aureus 491                                                                     2   4   0.5 16   1   4    2   1    0.25                                                                               1   2                    Staphylococcus aureus S13E                                                                    2   8   0.5 8    0.5 8    0.25                                                                               4    0.5 1   1                    Staphylococcus aureus SA1199                                                                  4   2   0.25                                                                               8    2   8    0.5 8    0.25                                                                               2   4                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       2   ≦0.06                                                                       4    ≦0.06                                                                       8    ≦0.06                                                                       0.5  ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 1       0.25                                                                               8    2        4   8    0.25                                                                               1   1                    Staphylococcus haemolyticus 105                                                               8   8   4   >64  4   16   8   4    0.5 8   8                    Staphylococcus haemolyticus 415                                                               16  8   4   >64  2   32   1   8    2   4   8                    Staphylococcus epidermidis 270                                                                4   4   16  >64  2   0.125                                                                               8   4    1   2   4                    Entercoccus faecium 180                                                                       2   1   1   8    1   4    2   1    0.5 1   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.5 ≦0.06                                                                       4    ≦0.06                                                                       4    ≦0.06                                                                       1    ≦0.06                                                                       0.125                                                                              ≦0.06         Entercoccus faecalis 2041                                                                     0.125                                                                              4   0.25                                                                               16   0.5 16   0.125                                                                              2    ≦0.06                                                                       0.5 0.25                 Entercoccus faecalis 276                                                                      1   4   0.26                                                                               18   1   4    0.5 4    ≦0.06                                                                       2   0.5                  Entercoccus gallinarum 245                                                                    0.5 8   0.25                                                                               8    ≦0.06                                                                       32   0.25                                                                               0.25 ≦0.06                                                                       1   0.5                  Haemophilus influenzae RD                                                                     16  >64 ≦0.06 64   32               32                   Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5  ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06             __________________________________________________________________________     Organism       18  19  20  21   22  23   24  25   26  27  28                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   0.5 0.5 >64  16  38   0.5 0.5  0.25                                                                               2   0.25                 Staphylococcus aureus 489                                                                     1   0.25                                                                               0.5 32   8   >64  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     8   1   4   >64  16  16   1   0.25 2   8   1                    Staphylococcus aureus X400                                                                    1   0.25                                                                               0.5 32   8   16   0.25                                                                               ≦0.06                                                                        0.25                                                                               0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 0.25                                                                               0.25                                                                               32   8   16   0.125                                                                              ≦0.06                                                                        0.125                                                                              0.5 ≦0.06         Staphylococcus aureus 491                                                                     2   2   1   64   8   16   0.5 0.125                                                                               0.5 1   0.25                 Staphylococcus aureus S13E                                                                    1   ≦0.06                                                                       ≦0.06                                                                       64   16  16   ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.125                                                                              ≦0.06         Staphylococcus aureus SA1199                                                                  2   0.5 2   64   16  16   0.5 ≦0.06                                                                        1   0.5 0.125                Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       16   4   16   ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   1   0.5 64   16  16   2   0.125                                                                               0.5 1   0.125                Staphylococcus haemolyticus 105                                                               16  4   8   >64  16  4    4   1    4   16  4                    Staphylococcus haemolyticus 415                                                               8   8   4   64   16  16   ≦0.06                                                                       32   8   8   8                    Staphylococcus epidermidis 270                                                                8   2   2   32   4   64   1   0.5  1   4   1                    Entercoccus faecium 180                                                                       2   1   1   8    1   >64  4   0.5  4   8   1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       8    ≦0.06                                                                       32   ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.5 ≦0.06         Entercoccus faecalis 2041                                                                     0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       32   2   32   ≦0.06                                                                       0.25 0.25                                                                               0.125                                                                              0.25                 Entercoccus faecalis 276                                                                      1   ≦0.06                                                                       0.25                                                                               64   4   32   0.25                                                                               0.25 ≦0.06                                                                       0.5 ≦0.06         Entercoccus gallinarum 245                                                                    1   ≦0.06                                                                       0.25                                                                               8    1   8    0.25                                                                               ≦0.06                                                                        0.125                                                                              0.5 0.25                 Haemophilus influenzae RD                                                                     16  32  8   >64  64  >64  >64 32   >64 >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       2    ≦0.06                                                                       1    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06             Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5  0.25                                                                               0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06             __________________________________________________________________________     Organism       29  30  31  32   33  34   35  36   37  38  39                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   1   0.5 1    4   32   0.5 8    0.5 0.5 0.125                Staphylococcus aureus 489                                                                     1   0.125                                                                              ≦0.06                                                                       1    ≦0.06                                                                       8    ≦0.06                                                                       2    0.125                                                                              ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     0.25                                                                               2   0.5 0.5  0.125                                                                              8    0.125                                                                              2    0.125                                                                              0.125                                                                              0.25                 Staphylococcus aureus X400                                                                    0.25                                                                               ≦0.06                                                                       0.125                                                                              0.5  0.25                                                                               32   0.25                                                                               4    0.25                                                                               1   ≦0.06         Staphylococcus aureus X778                                                                    ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              0.5  0.5 16   ≦0.06                                                                       2    ≦0.06                                                                       0.5 ≦0.06         Staphylococcus aureus 491                                                                     0.25                                                                               0.5 0.5 0.25 0.125                                                                              8    0.125                                                                              1    0.25                                                                               0.5 0.25                 Staphylococcus aureus S13E                                                                    1   0.125                                                                              0.25                                                                               1    ≦0.06                                                                       16   ≦0.06                                                                       2    ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               0.5 0.25                                                                               1    1   16   0.25                                                                               4    0.25                                                                               1   ≦0.06         Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.25                                                                               0.125                                                                              0.25                                                                               0.125                                                                               0.125                                                                              16   0.25                                                                               4    ≦0.06                                                                       0.125                                                                              ≦0.06         Staphylococcus haemolyticus 105                                                               4   4   4   4    2   32   2   4    0.25                                                                               1   2                    Staphylococcus haemolyticus 415                                                               1   16  16  4    8   >64  4   8    1   1   4                    Staphylococcus epidermidis 270                                                                0.5 2   1   1    2   16   1   2    0.25                                                                               0.5 0.25                 Entercoccus faecium 180                                                                       0.25                                                                               2   4   0.25 2   4    1   0.25 0.125                                                                              ≦0.06                                                                       0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     0.25                                                                               ≦0.06                                                                       0.25                                                                               0.25 ≦0.06                                                                       8    ≦0.06                                                                       1    0.125                                                                              ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      0.25                                                                               0.25                                                                               0.25                                                                               0.125                                                                               ≦0.06                                                                       16   ≦0.06                                                                       2    1   0.5 ≦0.06         Entercoccus gallinarum 245                                                                    0.25                                                                               ≦0.06                                                                       0.25                                                                               0.25 0.25                                                                               4    ≦0.06                                                                       0.25 0.125                                                                              0.125                                                                              ≦0.06         Haemophilus influenzae RD                                                                     >64 >64 >64 >64                                                 Escherichia coli EC14                                                                         64  >64 >64 32   >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       40  41  42  43   44  45   46  47   48  49  50                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     4   2   1   0.5  0.25                                                                               1    1   0.125                                                                               0.125                                                                              0.5 0.5                  Staphylococcus aureus 489                                                                     4   ≦0.06                                                                       0.5 ≦0.06                                                                        ≦0.06                                                                       0.5  1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     2   0.25                                                                               0.5 2    1   16   2   2    2   1   0.5                  Staphylococcus aureus X400                                                                    4   ≦0.06                                                                       1   0.25 ≦0.06                                                                       0.25 2   ≦0.06                                                                        ≦0.06                                                                       0.125                                                                              0.125                Staphylococcus aureus X778                                                                    4   0.125                                                                              1   ≦0.06                                                                        ≦0.06                                                                       0.25 2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.125                Staphylococcus aureus 491                                                                     4   0.5 0.5 1    0.125                                                                              1    2   0.5  0.25                                                                               0.125                                                                              0.5                  Staphylococcus aureus S13E                                                                    4   ≦0.06                                                                       0.5 0.25 0.25                                                                               0.5  2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.125                Staphylococcus aureus SA1199                                                                  4   ≦0.06                                                                       1   0.5  0.25                                                                               2    2   0.5  0.25                                                                               2   1                    Staphylococcus aureus SA1199A                                                                 0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 0.25 ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 8   0.25                                                                               2   0.5  0.25                                                                               1    2   0.25 1   1   2                    Staphylococcus haemolyticus 105                                                               2   2   2   4    2   16   2   4    2   1   0.5                  Staphylococcus haemolyticus 415                                                               2   4   1   8    4   8    2   16   8   1   1                    Staphylococcus epidermidis 270                                                                1   0.25                                                                               0.5 2    0.5 8    2   1    1   1   0.5                  Entercoccus faecium 180                                                                       1   0.25                                                                               0.25                                                                               4    8   1    0.5 2    1   0.25                                                                               0.25                 Entercoccus faecium 180-1                                                                     2   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     1   ≦0.06                                                                       0.125                                                                              0.5  ≦0.06                                                                       0.125                                                                               1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      2   ≦0.06                                                                       8   0.5  0.125                                                                              0.25 0.5 ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               0.25                 Entercoccus gallinarum 245                                                                    11  ≦0.06                                                                       1   0.5  0.5 0.5  0.25                                                                               16   1   1   1                    Haemophilus influenzae RD       >64 >64  >64 >64  >64 >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                        Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       51  52  53  54   55  56   57  58   59  60  61                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.25                                                                               ≦0.06                                                                       2   1    0.5 0.5  0.25                                                                               0.25 0.5 1   0.5                  Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.5 2   ≦0.06                                                                        1   1    0.5 ≦0.06                                                                        0.125                                                                              0.5 1                    Staphylococcus aureus 447                                                                     0.5 ≦0.06                                                                       4   0.25 4   2    0.5 1    1   2   2                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       4   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        0.25                                                                               0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 0.5 2   ≦0.06                                                                        0.5 0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               0.125                Staphylococcus aureus 491                                                                     0.25    2        0.5 0.5      0.125    1   0.5                  Staphylococcus aureus S13E                                                                    0.5 0.5 2   0.5  0.5 0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.25                                                                               0.125                Staphylococcus aureus SA1199                                                                  0.5 2   2   0.5  0.5 0.5  1   1    ≦0.06                                                                       0.5 0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 1   2   2   1    0.5 0.5  0.125                                                                              0.125                                                                               0.5 0.5 0.25                 Staphylococcus haemolyticus 105                                                               0.5 0.5 2   2    4   4    8   4    8   >64 64                   Staphylococcus haemolyticus 415                                                               1   1   2   1    16  16   1   8    8   16  8                    Staphylococcus epidermidis 270                                                                0.5 0.5 2   0.25 1   1    0.5 4    1   2   1                    Entercoccus faecium 180                                                                       0.5 2   1   1    2   2    0.5 8    8   4   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       0.5 1   ≦0.06                                                                        0.125                                                                              0.25 ≦0.06                                                                       0.5  0.5 0.25                                                                               ≦0.06         Entercoccus faecalis 276                                                                      ≦0.06                                                                       0.125                                                                              8   1    0.5 0.25 0.5 0.5  0.125                                                                              0.5 0.25                 Entercoccus gallinarum 245                                                                    1   1   2   0.5  16  16   2   0.5  1   16  8                    Haemophilus influenzae RD                                                                     >64 >64 >64      >64 >64  >64 >64  >64 >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                 Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       62  63  64  65   66  67   68  69   70  71  72                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   0.5 0.25                                                                               2    0.25                                                                               0.25 0.125                                                                              1    0.125                                                                              4   2                    Staphylococcus aureus 489                                                                     2   8   0.25                                                                               0.125                                                                               1   ≦0.06                                                                        0.125                                                                              0.25 ≦0.06                                                                       0.25                                                                               ≦0.06         Staphylococcus aureus 447                                                                     0.5 1   0.5 1    1   1    0.25                                                                               1    0.5 4   1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              0.125                                                                               0.125                                                                              1    ≦0.06                                                                       0.5  ≦0.06                                                                       1   0.125                Staphylococcus aureus X778                                                                    0.5 0.125                                                                              2   0.5  ≦0.06                                                                       0.25 ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       2   0.25                 Staphylococcus aureus 491                                                                     0.125                                                                              0.5 0.125                                                                              0.5  0.25                                                                               1    0.125                                                                              1    0.5 2   0.25                 Staphylococcus aureus S13E                                                                    0.5 0.125                                                                              2   0.5  ≦0.06                                                                       0.25 ≦0.06                                                                       0.25 ≦0.06                                                                       1   ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               0.25                                                                               1   0.5  0.25                                                                               1    ≦0.06                                                                       1    ≦0.06                                                                       1   1                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               ≦0.06         Staphylococcus aureus SA1199B                                                                 1   0.5 0.125                                                                              2    0.25                                                                               1    0.5 2    ≦0.06                                                                       4   ≦0.06         Staphylococcus haemolyticus 105                                                               2   4   64  64   64  64   2   4    2   16  1                    Staphylococcus haemolyticus 415                                                               4   8   2   4    8   2    4   8    2   8   4                    Staphylococcus epidermidis 270                                                                1   1   0.5 1    1   0.5  2   2    0.25                                                                               2   0.25                 Entercoccus faecium 180                                                                       4   16  0.125                                                                              0.5  2   0.25 2   4    0.5 4   0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       1   ≦0.06         Entercoccus faecalis 276                                                                      0.5 0.5 0.5 0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5  ≦0.06                                                                       2   ≦0.06         Entercoccus gallinarum 245                                                                    4   8   2   4    8   2    4   8    2   8   4                    Haemophilus influenzae RD                                                                     >64 >64 >64 >64  >64 >64  >64 >64  16  >64 32                   Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                               __________________________________________________________________________     Organism       73  74  75  76   77  78   79  80   81  82  83                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.25                                                                               4   2   0.25 ≦0.06                                                                       2    2   4    2   2   1                    Staphylococcus aureus 489                                                                     0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        2   2    2   0.25                                                                               0.25                 Staphylococcus aureus 447                                                                     0.25                                                                               1   1   0.5  1   ≦0.06                                                                        2   2    2   4   2                    Staphylococcus aureus X400                                                                    0.5 ≦0.06                                                                       ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               4    1   0.25                                                                               2                    Staphylococcus aureus X778                                                                    1   ≦0.06                                                                       ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        2   0.5  1   0.5 0.5                  Staphylococcus aureus 491                                                                     0.25                                                                               0.125                                                                              0.25                                                                               0.25     0.25 4   1    1   1   0.5                  Staphylococcus aureus S13E                                                                        0   0        0.125    4   1    0.5 ≦0.06                                                                       0.125                Staphylococcus aureus SA1199                                                                  0.5 ≦0.06                                                                       2   ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               1   2    2   0.25                                                                               2                    Staphylococcus aureus SA1199A                                                                 0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              1    0.5 0.5 0.25                 Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       1   0.5 0.25 0.125                                                                              ≦0.06                                                                        1   1    1   1   1                    Staphylococcus haemolyticus 105                                                               0.5 4   2   2    2   2    4   4    1   8   2                    Staphylococcus haemolyticus 415                                                               2   4   4   4    8   16   4   4    4   8   4                    Staphylococcus epidermidis 270                                                                0.125                                                                              0.5 0.5 0.25 0.5 0.5  0.5 2    1   4   2                    Entercoccus faecium 180                                                                       0.5 0.5 0.5 0.5  8   1    ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       2   8                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.125                                                                              0.125                Entercoccus faecalis 2041                                                                     0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5 0.5                  Entercoccus faecalis 276                                                                      0.25    ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06             Entercoccus gallinarum 245                                                                    2   ≦0.06                                                                       4   4    0.25                                                                               0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.125                                                                              0.5                  Haemophilus influenzae RD                                                                     0.25                                                                               0.5 2   >64  64       16  16   16  64  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       84  85  86  87   88  89   90  91   92  93  94                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.125                                                                              1   1    0.25                                                                               0.5  2   0.5  2   2   1                    Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.25                                                                               1   0.5  0.5 0.25 2   ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               2                    Staphylococcus aureus 447                                                                     4   0.125                                                                              0.5 0.5  0.25                                                                               1    1   0.5  0.5 0.25                                                                               0.5                  Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.25                                                                               1   1    ≦0.06                                                                       0.25 1   0.5  0.5 ≦0.06                                                                       1                    Staphylococcus aureus X778                                                                    ≦0.06                                                                       0.25                                                                               1   2    0.5 0.25 1   ≦0.06                                                                        0.25                                                                               1   0.5                  Staphylococcus aureus 491                                                                     1   0.125                                                                              1   2    0.5 1    2   1    1   0.25                                                                               0.5                  Staphylococcus aureus S13E                                                                    0.125                                                                              0.5 1   0.5  1   0.25 1   ≦0.06                                                                        0.125                                                                              1   2                    Staphylococcus aureus SA1199                                                                  0.25                                                                               0.5 0.5 2    1   0.5  2   ≦0.06                                                                        1   2   0.5                  Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.5 1   1   0.5  1   1    1   0.5  0.5 1   2                    Staphylococcus haemolyticus 105                                                               8   1   1   1    1   1    2   2    2   1   2                    Staphylococcus haemolyticus 415                                                               16  2   1   2    2   2    2   2    2   1   2                    Staphylococcus epidermidis 270                                                                1   0.5 1   1    1   1    1   0.5  1   1   1                    Entercoccus faecium 180                                                                       4   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.125                                                                               0.25                                                                               0.5  0.125                                                                              ≦0.06                                                                       0.25                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        0.125                                                                              ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                          0.125                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        2   ≦0.06                                                                        0.125                                                                              0.25                                                                               0.125                Entercoccus gallinarum 245                                                                    0.25                                                                               2   1   2    ≦0.06                                                                       ≦0.06                                                                        2   2    2   1   2                    Haemophilus influenzae RD                >64                                   Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       95  96  97  98   99  100  101 102  103 104 105                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 1   1   0.5  0.5 1    0.5 1    0.5 ≦0.06                                                                       0.25                 Staphylococcus aureus 489                                                                     2   1   0.25                                                                               ≦0.06                                                                        0.25                                                                               0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.5                  Staphylococcus aureus 447                                                                     0.5 1   1   0.25 2   0.5  1   1    1   0.25                                                                               0.5                  Staphylococcus aureus X400                                                                    1   2   1   ≦0.06                                                                        0.125                                                                              1    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.5                  Staphylococcus aureus X778                                                                    1   1   0.25                                                                               ≦0.06                                                                        0.5 1    0.25                                                                               ≦0.06                                                                        0.5 ≦0.06                                                                       0.5                  Staphylococcus aureus 491                                                                     1   1   0.5 0.25 1   ≦0.06                                                                        0.5 1    1   ≦0.06                                                                       0.25                 Staphylococcus aureus S13E                                                                    2   1   >64 0.5  0.5 1    0.25                                                                               1    1   ≦0.06                                                                       0.5                  Staphylococcus aureus SA1199                                                                  0.5 2   2   0.5  0.5 0.5  0.25                                                                               0.125                                                                               1   2   1                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.5 0.125                                                                               0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.25                 Staphylococcus aureus SA1199B                                                                 1   1   1   1    0.5 0.5  1   1    2   0.125                                                                              0.5                  Staphylococcus haemolyticus 105                                                               1   2   2   1    8   1    1   2    4   2   1                    Staphylococcus haemolyticus 415                                                               1   2   2   1    32  2    8   4    8   2   1                    Staphylococcus epidermidis 270                                                                1   2   1   ≦0.06                                                                        1   0.5  0.5 1    1   0.25                                                                               0.25                 Entercoccus faecium 180                                                                       0.5 0.5                                ≦0.06                                                                       0.25                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       1   ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       0.25                 Entercoccus faecalis 276                                                                      0.125                                                                              0.5 ≦0.06                                                                       0.125                                                                               0.25                                                                               0.25 0.125                                                                              0.25 0.25                                                                               ≦0.06                                                                       0.25                 Entercoccus gallinarum 245                                                                    1   2   2   1    32  2    8   4    8   2   1                    Haemophilus influenzae RD       >64 >64  >64          32  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       106 107 108 109  110 111  112 113  114 115 116                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   2   2   1    0.5 2    2   ≦0.06                                                                        0.5 0.125                                                                              0.5                  Staphylococcus aureus 489                                                                     2   1   0.25                                                                               ≦0.06                                                                        1   1    0.25                                                                               0.125                                                                               1   0.125                                                                              1                    Staphylococcus aureus 447                                                                     0.25                                                                               1   0.5 1    1   1    1   0.25 0.5 0.5 1                    Staphylococcus aureus X400                                                                    1   1   2   ≦0.06                                                                        1   1    1   0.125                                                                               2   1   1                    Staphylococcus aureus X778                                                                    1   0.5 0.125                                                                              ≦0.06                                                                        0.5 2    1   1    2   1   2                    Staphylococcus aureus 491                                                                     0.5 1   0.25                                                                               0.25 0.25                                                                               2    1   0.25 1   0.5 0.5                  Staphylococcus aureus S13E                                                                    1   2   1   0.25 1   1    1   ≦0.06                                                                        2   0.25                                                                               1                    Staphylococcus aureus SA1199                                                                  1   1   2   ≦0.06                                                                        0.25                                                                               2    2   1    2   0.125                                                                              4                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   2   2   0.5  0.5 1    0.5 ≦0.06                                                                        1   0.25                                                                               0.5                  Staphylococcus haemolyticus 105                                                               1   2   2   1    4   1    2   4    2   1   2                    Staphylococcus haemolyticus 415                                                               1   2   1   4    2   4    2   1    2   2   4                    Staphylococcus epidermidis 270                                                                0.25                                                                               0.5 0.125                                                                              0.25 2   1    1   0.25 1   0.5 1                    Entercoccus faecium 180                                                                       ≦0.06                                                                       0.125                                                                              0.125                                                                              0.25 0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1   ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     0.125                                                                              0.5 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      0.5 1   0.5 ≦0.06                                                                        0.5 0.5  0.5 0.25 1   0.125                                                                              0.25                 Entercoccus gallinarum 245                                                                    1   2   ≦0.06                                                                       ≦0.06                                                                        2   4    2   1    2   2   4                    Haemophilus influenzae RD                                                                     >64 >64 >64 32   >64 >64  >64 >64  >64 >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64      >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       117 118 119 120  121 122  123 124  125 126 127                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 1   2   2    2   1    2   4    4   2   1                    Staphylococcus aureus 489                                                                     0.125                                                                              0.25                                                                               0.5 2    1   ≦0.06                                                                        2   0.25 2   0.25                                                                               2                    Staphylococcus aureus 447                                                                     0.5 0.25                                                                               2   1    0.5 0.25 1   0.25 2   1   2                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.25                                                                               1   0.25 0.125                                                                              ≦0.06                                                                        1   1    1   1   2                    Staphylococcus aureus X778                                                                    0.25                                                                               0.5 2   0.125                                                                               0.5 ≦0.06                                                                        1   0.5  2   0.5 1                    Staphylococcus aureus 491                                                                     0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               1   0.25                                                                               1                    Staphylococcus aureus S13E                                                                    ≦0.06                                                                       0.25                                                                               0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   0.5 2                    Staphylococcus aureus SA1199                                                                  ≦0.06                                                                       2   2   1    1   ≦0.06                                                                        2   1    0.5 0.125                                                                              2                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        0.25                                                                               0.25                                                                               0.25                 Staphylococcus aureus SA1199B                                                                 0.5 ≦0.06                                                                       0.5 0.125                                                                               0.25                                                                               ≦0.06                                                                        0.5 ≦0.06                                                                        2   1   2                    Staphylococcus haemolyticus 105                                                               1   1   2   2    2   1    2   2    4   0.5 2                    Staphylococcus haemolyticus 415                                                               2   1   2   2    2   1    1   1    2   2   4                    Staphylococcus epidermidis 270                                                                0.5 1   2   2    1   ≦0.06                                                                        1   0.25 1   1   ≦0.06         Entercoccus faecium 180                                                                       1   0.125                                                                              0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        1   1   ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      0.25                                                                               ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        2   1   ≦0.06         Entercoccus gallinarum 245                                                                    2   1   2   2    2   1    1   1    12  2   4                    Haemophilus influenzae RD                                                                         16  16  16   16  16   16  16           >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       128 129 130 131  132 133  134 135  136 137 138                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     4   2   1   2    1   2    2   1    ≦0.06                                                                       0.25                                                                               0.125                Staphylococcus aureus 489                                                                     1   ≦0.06                                                                       0.5 1    1   1    0.5 0.125                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     1   1   1   1    2   1    1   1    2   4   2                    Staphylococcus aureus X400                                                                    1   0.25                                                                               0.5 1    1   0.5  0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.0606       Staphylococcus aureus X778                                                                    1   0.25                                                                               1   0.5  2   2    1   1    ≦0.06                                                                       ≦0.06                                                                       0.25                 Staphylococcus aureus 491                                                                     2   0.5 0.5 0.125                                                                               0.5 0.25 0.5 0.25 0.25                                                                               0.25                                                                               0.125                Staphylococcus aureus S13E                                                                    1   0.25                                                                               0.5 1    2   1    2   1    ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199                                                                  0.5 0.25                                                                               1   0.25 1   0.25 0.25                                                                               1    ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199A                                                                 0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.25 0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   0.25                                                                               2   1    2   2    2   0.25 ≦0.06                                                                       ≦0.06                                                                       0.5                  Staphylococcus haemolyticus 105                                                               1   4   1   1    1   2    2   0.5  2   2   4                    Staphylococcus haemolyticus 415                                                               2   4   2   2    2   2    4   2    4   8   8                    Staphylococcus epidermidis 270                                                                1   1   1   1    2   1    2   0.5  1   0.5 2                    Entercoccus faecium 180                                                                       1   4   1   ≦0.06                                                                        0.25                                                                               1    0.5 1    2   0.125                                                                              4                    Entercoccus faecium 180-1                                                                     0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     0.5 ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        1   0.25 0.25                                                                               0.125                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      1   0.125                                                                              1   0.25 1   1    1   0.5  ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus gallinarum 245                                                                    2   0.125                                                                              2   2    2   2    4   2    4   8   0.125                Haemophilus influenzae RD                                                                         >64                                                         Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       139 140 141 142  143 144  145 146  147 148 149                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.125                                                                              2   2    0.5 16   0.5 0.5  0.5 1   0.5                  Staphylococcus aureus 489                                                                     0.25                                                                               ≦0.06                                                                       0.25                                                                               0.5  ≦0.06                                                                       4    ≦0.06                                                                       0.25     0.25                                                                               ≦0.06         Staphylococcus aureus 447                                                                     1   0.25                                                                               1   2    4   16   1   2    0.125                                                                              1   4                    Staphylococcus aureus X400                                                                    0.25                                                                               ≦0.06                                                                       0.25                                                                               1    0.125                                                                              8    0.25                                                                               0.5  4   ≦0.06                                                                       ≦0.06         Staphylococcus aureus X778                                                                    0.125                                                                              0.25                                                                               0.5 1    ≦0.06                                                                       8    0.125                                                                              ≦0.06                                                                        0.25                                                                               2   0.5                  Staphylococcus aureus 491                                                                     0.5 0.25                                                                               0.5 0.5  0.5 8    0.5 1    ≦0.06                                                                       0.125                                                                              0.5                  Staphylococcus aureus S13E                                                                    ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               2    0.125                                                                              8    0.125                                                                              0.5  1   1   0.25                 Staphylococcus aureus SA1199                                                                  0.125                                                                              ≦0.06                                                                       0.25                                                                               1    0.125                                                                              8    0.25                                                                               ≦0.06                                                                        0.5 2   0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2    ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   ≦0.06                                                                       2   2    0.25                                                                               8    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5 1                    Staphylococcus haemolyticus 105                                                               4   2   1   1    8   64   2   2    1   1   4                    Staphylococcus haemolyticus 415                                                               8   8   4   1    32  >64  8   4    8   2   16                   Staphylococcus epidermidis 270                                                                1   0.25                                                                               1   0.25 1   16   1   2    16  0.5 1                    Entercoccus faecium 180                                                                       2   1   0.5 0.5  4   8    4   8    2   0.25                                                                               1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       4    ≦0.06                                                                       ≦0.06                                                                        2   ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              8    0.25                                                                               0.5  ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      1   0.5 0.5 1    0.25                                                                               8    0.125                                                                              1    0.125                                                                              ≦0.06                                                                       ≦0.06         Entercoccus gallinarum 245                                                                    8   8   4   1    32  4    0.25                                                                               0.5  0.125                                                                              2   16                   Haemophilus influenzae RD                    >64                               Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       150 151 152 153  154 155  156 157  158 159 160                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   2   2   0.5  2   2    2   0.5  2   0.5 2                    Staphylococcus aureus 489                                                                     0.5 ≦0.06                                                                       0.5 1    1   0.5  1   0.5  2   0.25                                                                               0.21                 Staphylococcus aureus 447                                                                     0.5 1   8   0.5  2   8    1   0.25 4   4   1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       1   0.5  2   1    2   0.5  4   4   4                    Staphylococcus aureus X778                                                                    2   1   0.5 0.5  0.5 ≦0.06                                                                        1   0.25 4   2   4                    Staphylococcus aureus 491                                                                     ≦0.06                                                                       0.5 1   0.125                                                                               0.5 1    1   ≦0.06                                                                        1   2   0.125                Staphylococcus aureus S13E                                                                    0.25                                                                               0.25                                                                               0.5 0.125                                                                               0.25                                                                               1    1   0.25 2   1   1                    Staphylococcus aureus SA1199                                                                  1   0.125                                                                              1   0.5  2   1    1   1    4   0.125                                                                              0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   ≦0.06                                                                       0.125                Staphylococcus aureus SA1199B                                                                 0.5 0.25                                                                               0.5 0.25 0.25                                                                               1    0.5 1    4   ≦0.06                                                                       ≦0.06         Staphylococcus haemolyticus 105                                                               1   1   16  2    4   16   4   1    4   16  8                    Staphylococcus haemolyticus 415                                                               2   4   16  1    4   16   2   1    8   8   8                    Staphylococcus epidermidis 270                                                                0.25                                                                               0.5 4   0.25 0.5 1    1   0.25 4   0.5 1                    Entercoccus faecium 180                                                                       0.25                                                                               0.25                                                                               4   0.125                                                                               1   4    1   ≦0.06                                                                        0.25                                                                               2   0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        0.125                                                                              0.125                                                                               0.5 ≦0.06                                                                        1   0.125                                                                              ≦0.06         Entercoccus faecalis 276                                                                      1   ≦0.06                                                                       0.25                                                                               0.5  0.5 0.25 2   ≦0.06                                                                        2   0.125                                                                              2                    Entercoccus gallinarum 245                                                                    2   4   16  1    4   16   2   1    8   8   8                    Haemophilus influenzae RD           16   2                                     Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       161 162 163 164  165 166  167 168  169 170 171                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.5 1   2    1   2    1   ≦0.06                                                                        0.25                                                                               2   1                    Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.25                                                                               8   2    2   2    16  0.125                                                                               ≦0.06                                                                       0.25                                                                               0.5                  Staphylococcus aureus 447                                                                     1   ≦0.06                                                                       0.5 2    0.5 2    4   ≦0.06                                                                        2   0.5 1                    Staphylococcus aureus X400                                                                    0.5 ≦0.06                                                                       0.5 0.5  0.5 1    1   ≦0.06                                                                        ≦0.06                                                                       0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 ≦0.06                                                                       2   1    0.125                                                                              1    16  0.5  ≦0.06                                                                       1   ≦0.06         Staphylococcus aureus 491                                                                     0.5 0.25                                                                               ≦0.06                                                                       1    0.5 0.5  2   0.5  0.25                                                                               0.5 0.25                 Staphylococcus aureus S13E                                                                    0.125                                                                              ≦0.06                                                                       1   4    ≦0.06                                                                       4    4   ≦0.06                                                                        ≦0.06                                                                       0.25                                                                               ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               ≦0.06                                                                       2   2    0.25                                                                               2    2   0.5  ≦0.06                                                                       1   0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.5 0.5  ≦0.06                                                                       0.125                                                                               4   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.25                                                                               ≦0.06                                                                       1   2    1   2    4   1    0.125                                                                              0.25                                                                               0.25                 Staphylococcus haemolyticus 105                                                               4   0.25                                                                               8   2    4   2    32  0.5  2   4   4                    Staphylococcus haemolyticus 415                                                               8   2   8   2    4   2    16  2    4   4   8                    Staphylococcus epidermidis 270                                                                1   ≦0.06                                                                       4   1    1   0.5  8   0.125                                                                               0.25                                                                               1   1                    Entercoccus faecium 180                                                                       2   ≦0.06                                                                       1   0.5  0.5 0.25 2   0.25 1   2   1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       ≦0.06                                                                       1   1    ≦0.06                                                                       ≦0.06                                                                        8   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      0.125                                                                              ≦0.06                                                                       1   1    0.5 0.5  4   0.125                                                                               ≦0.06                                                                       0.5 0.125                Entercoccus gallinarum 245                                                                    8   2   8   2    4   2    16  2    4   4   8                    Haemophilus influenzae RD                             >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       172 173 174 175  176 177  178 179  180 181 182                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     4   4   0.5 1    2   0.5  1   0.125                                                                               0.125                                                                              ≦0.06                                                                       2                    Staphylococcus aureus 489                                                                     0.5 2   ≦0.06                                                                       0.25 0.5 ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       2                    Staphylococcus aureus 447                                                                     0.5 4   4   1    1   4    0.5 0.25 0.125                                                                              ≦0.06                                                                       0.25                 Staphylococcus aureus X400                                                                    0.5 4   ≦0.06                                                                       0.125                                                                               1   ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       1                    Staphylococcus aureus X778                                                                    2   4   ≦0.06                                                                       0.5  1   2    1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       2                    Staphylococcus aureus 491                                                                     0.5 2   1   0.5  2   0.5  0.125                                                                              0.125                                                                               0.5     1                    Staphylococcus aureus S13E                                                                    ≦0.06                                                                       4   ≦0.06                                                                       0.25 2   0.25 0.5 0.25 ≦0.06                                                                       ≦0.06                                                                       0.25                 Staphylococcus aureus SA1199                                                                  1   2   ≦0.06                                                                       ≦0.06                                                                        2   0.25 1   1    0.125                                                                              ≦0.06                                                                       2                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       0.5 ≦0.06                                                                       0.5  >64 0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       4   0.125                                                                              ≦0.06                                                                        1   0.25 1   0.125                                                                               ≦0.06                                                                       ≦0.06                                                                       4                    Staphylococcus haemolyticus 105                                                               0.25                                                                               2   4   2    4   4    1   0.5  2   0.25                                                                               2                    Staphylococcus haemolyticus 415                                                               2   4   16  4    2   16   2   1    2   1   4                    Staphylococcus epidermidis 270                                                                0.5 2   2   0.5  0.5 1    0.25                                                                               0.25 0.125                                                                              0.125                                                                              0.25                 Entercoccus faecium 180                                                                       0.5 0.5 2   1    2   4    0.25                                                                               ≦0.06                                                                        8   4   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.5 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       0.5 ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.25 ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.125                                                                              1                    Entercoccus faecalis 276                                                                      0.125                                                                              2   ≦0.06                                                                       ≦0.06                                                                        2   0.25 0.5 ≦0.06                                                                        2   2   1                    Entercoccus gallinarum 245                                                                    2   4   16  4    2   16   2   1    0.25                                                                               ≦0.06                                                                       1                    Haemophilus influenzae RD                                                                     32  >64 >64 16   8   >64  4   4        32  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5  0.25                                                                               16   ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5  0.25                                                                               8    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       183 184 185 186  189 190  191 192  193 194 195                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     ≦0.06                                                                       2   ≦.06                                                                        ≦.06                                                                         0.5 0.25 2   0.5  0.5 ≦0.06                                                                       0.5                  Staphylococcus aureus 489                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                         1   0.125                                                                               2   1    0.125                                                                              0.125                                                                              1                    Staphylococcus aureus 447                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                         0.5 1    2   2    ≦0.06                                                                       0.5 1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.5 ≦.06                                                                        ≦.06                                                                         0.125                                                                              ≦0.06                                                                        1   1    0.25                                                                               ≦0.06                                                                       2                    Staphylococcus aureus X778                                                                    ≦0.06                                                                       0.5 ≦.06                                                                        ≦.06                                                                         0.25                                                                               0.125                                                                               2   1    ≦0.06                                                                       0.5 0.5                  Staphylococcus aureus 491                                                                     0.125                                                                              0.5 ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       0.125                                                                               1   0.5  ≦0.06                                                                       ≦0.06                                                                       0.5                  Staphylococcus aureus S13E                                                                    ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                         0.5 0.125                                                                               2   1    ≦0.06                                                                       ≦0.06                                                                       2                    Staphylococcus aureus SA1199                                                                  ≦0.06                                                                       0.125                                                                              ≦.06                                                                        ≦.06                                                                         0.5 0.25 2   2    0.125                                                                              0.5 0.5                  Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.5 0.25 ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                         1   0.5  2   0.5  0.125                                                                              0.125                                                                              1                    Staphylococcus haemolyticus 105                                                               ≦0.06                                                                       0.25                                                                               ≦.06                                                                        0.5  1   8    2   1    0.5 1   1                    Staphylococcus haemolyticus 415                                                               ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        1    1   8    8   2    1   2   4                    Staphylococcus epidermidis 270                                                                ≦0.06                                                                       4   ≦.06                                                                        0.125                                                                               0.25                                                                               2    2   1    0.25                                                                               0.5 0.25                 Entercoccus faecium 180                                                                       2   8   0.125                                                                              2    0.125                                                                              8    4   0.25 ≦0.06                                                                       ≦0.06                                                                       0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.1  ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 2041                                                                     ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        1   0.125                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Entercoccus faecalis 276                                                                      0.125                                                                              0.5 ≦.06                                                                        ≦.06                                                                         0.25                                                                               0.125                                                                               4   0.5  ≦0.06                                                                       0.125                                                                              0.25                 Entercoccus gallinarum 245                                                                    0.5 4   ≦.06                                                                        2    1   8    8   2    1   2   4                    Haemophilus influenzae RD                                                                     >64 64  8   32   >64 >64  >64 >64  >64 32                       Escherichia coli EC14                                                                         >64 >64 >64 >64  >64 >64  >64 >64  >64 >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                           ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                           ≦.06                                                                        ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       196  197  198  199  200  201  202  203  204 205                 __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5  1    1    0.5  1    4    4    0.5  0.125                                                                              2                   Staphylococcus aureus 489                                                                     1    2    0.125                                                                               2    0.25 8    4    0.5  0.25                                                                               0.5                 Staphylococcus aureus 447                                                                     0.5  2    0.125                                                                               1    0.5  16   8    1    ≦0.06                                                                       0.5                 Staphylococcus aureus X400                                                                    0.5  2    0.5  2    1    4    4    1    0.125                                                                              0.5                 Staphylococcus aureus X778                                                                    1    2    0.125                                                                               1    0.5  4    4    1    0.5 0.5                 Staphylococcus aureus 491                                                                     0.25 1    ≦0.06                                                                        0.5  0.125                                                                               4    8    1    ≦0.06                                                                       0.5                 Staphylococcus aureus S13E                                                                    1    2    0.125                                                                               0.5  0.5  8    4    2    0.5 0.5                 Staphylococcus aureus SA1199                                                                  0.5  2    0.5  1    1    8    8    2    0.125                                                                              1                   Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                        1    ≦0.06                                                                        0.125                                                                               ≦0.06                                                                        2    2    0.5      ≦0.06        Staphylococcus aureus SA1199B                                                                 0.5  2    0.5  1    1    16   8    1    0.25                                                                               0.5                 Staphylococcus haemolyticus 105                                                               0.5  1    0.5  2    1    8    4    1    0.5 1                   Staphylococcus haemolyticus 415                                                               1    4    1    4    2    8    8    2    0.25                                                                               1                   Staphylococcus epidermidis 270                                                                0.25 0.5  0.25 0.5  0.25 4    4    0.5  ≦0.06                                                                       0.125               Entercoccus faecium 180                                                                       0.5  0.5  ≦0.06                                                                        0.5  0.25 0.5  0.5  0.125                                                                               0.25                                                                               0.5                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                        0.25 ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.5  0.5  ≦0.06                                                                        0.125                                                                              ≦0.06        Entercoccus faecalis 2041                                                                     ≦0.06                                                                        0.25 ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        1    1    0.25 ≦0.06                                                                       0.25                Entercoccus faecalis 276                                                                      0.25 1    0.25 1    0.5  4    4    0.5  ≦0.06                                                                       0.5                 Entercoccus gallinarum 245                                                                    1    4    1    4    2    8    8    2    0.25                                                                               1                   Haemophilus influenzae RD                                                                     32   32   32   32   32   32   32   16   2   16                  Escherichia coli EC14                                                                         >64  >64  >64  >64  >64  >64  >64  >64  >64 >64                 Streptococcus pyogenes C203                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        Streptococcus pneumoniae P1                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        __________________________________________________________________________     Organism       206  207  208  209  210  211  212  213  214 215                 __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5  8    1    1    2    1    ≦0.06                                                                        ≦0.06                                                                        1   0.5                 Staphylococcus aureus 489                                                                     1    4    0.5  1    1    0.25 ≦0.06                                                                        ≦0.06                                                                        1   2                   Staphylococcus aureus 447                                                                     0.5  8    1    1    0.5  0.5  0.25 0.25 2   0.5                 Staphylococcus aureus X400                                                                    0.5  8    0.25 1    ≦0.06                                                                        0.5  ≦0.06                                                                        ≦0.06                                                                        0.5 0.5                 Staphylococcus aureus X778                                                                    0.5  8    0.125                                                                               1    1    1    ≦0.06                                                                        ≦0.06                                                                        1   ≦0.06        Staphylococcus aureus 491                                                                     ≦0.06                                                                        1    0.5  0.25 ≦0.06                                                                        0.25 ≦0.06                                                                        ≦0.06                                                                        1   0.25                Staphylococcus aureus S13E                                                                    1    8    0.25 0.5  ≦0.06                                                                        0.5  ≦0.06                                                                        ≦0.06                                                                        1   2                   Staphylococcus aureus SA1199                                                                  0.5  8    0.5  0.25 0.5  0.5  ≦0.06                                                                        ≦0.06                                                                        0.5 ≦0.06        Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                        4    ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.125                                                                               ≦0.06                                                                        ≦0.06                                                                        0.5 0.5                 Staphylococcus aureus SA1199B                                                                 1    16   0.5  0.5  0.125                                                                               1    ≦0.06                                                                        ≦0.06                                                                        1   1                   Staphylococcus haemolyticus 105                                                               0.5  8    0.25 0.5  1    0.5  1    0.5  1   2                   Staphylococcus haemolyticus 415                                                               1    1    2    1    1    0.5  1    2    2   1                   Staphylococcus epidermidis 270                                                                0.25 8    0.5  0.125                                                                               0.25 0.5  ≦0.06                                                                        0.5  ≦0.06                                                                       0.125               Entercoccus faecium 180                                                                       ≦0.06                                                                        1    0.25 ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.125                                                                               0.25                                                                               ≦0.06        Entercoccus faecium 180-1                                                                     ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        Entercoccus faecalis 2041                                                                     0.25 0.125                                                                               ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.125                                                                              0.25                Entercoccus faecalis 276                                                                      ≦0.06                                                                        0.25 0.125                                                                               0.25 ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.25                                                                               2                   Entercoccus gallinarum 245                                                                    1    1    2    1    1    ≦0.06                                                                        1    2    2   64                  Haemophilus influenzae RD                                                                               32   16   >64  >64  >64  32   32  >64                 Escherichia coli EC14                                                                         >64  >64  >64  >64  >64  >64  >64  >64  >64 >64                 Streptococcus pyogenes C203                                                                             ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06       ≦0.06        Streptococcus pneumoniae P1                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        __________________________________________________________________________     Organism       216  217  218  219  220  221  222  223  224 225                 __________________________________________________________________________     Staphylococcus aureus 446                                                                     1    0.25 4    8    1    1         0.25 0.5 1                   Staphylococcus aureus 489                                                                     1    ≦0.06                                                                        1    8    0.5  0.25 0.125                                                                               1    0.25                                                                               2                   Staphylococcus aureus 447                                                                     1    1    1    8    0.5  0.5  0.5  0.5  0.5 1                   Staphylococcus aureus X400                                                                    1    ≦0.06                                                                        0.25 8    0.5  0.5  0.125                                                                               1    0.125                                                                              1                   Staphylococcus aureus X778                                                                    0.25 ≦0.06                                                                        1    8    0.5  0.5  ≦0.06                                                                        1    0.125                                                                              0.5                 Staphylococcus aureus 491                                                                     1    0.25 0.5  4    ≦0.06                                                                        0.125                                                                               0.125                                                                               0.125                                                                               0.125                                                                              1                   Staphylococcus aureus S13E                                                                    1    ≦0.06                                                                        32   8    0.5  0.5  ≦0.06                                                                        0.5  0.25                                                                               1                   Staphylococcus aureus SA1199                                                                  ≦0.06                                                                        ≦0.06                                                                        4    4    1    1    1    2    0.25                                                                               1                   Staphylococcus aureus SA1199A                                                                 1    ≦0.06                                                                        ≦0.06                                                                        1    ≦0.06                                                                        ≦0.06                                                                        0.125                                                                               ≦0.06                                                                        ≦0.06                                                                       0.25                Staphylococcus aureus SA1199B                                                                 0.5  0.125                                                                               0.25 8    0.5  1    0.125                                                                               1    0.5 2                   Staphylococcus haemolyticus 105                                                               0.5  2    0.5  2    0.5  1    1    1    1   0.5                 Staphylococcus haemolyticus 415                                                               0.25 8    4    2    0.5  2    1    1    0.5 4                   Staphylococcus epidermidis 270                                                                0.125                                                                               0.5  1    4    1    0.125                                                                               0.5  0.5  0.25                                                                               1                   Entercoccus faecium 180                                                                       ≦0.06                                                                        2    ≦0.06                                                                        1    0.125                                                                               ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        Entercoccus faecium 180-1                                                                     ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        1    ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        Entercoccus faecalis 2041                                                                     0.25 ≦0.06                                                                        0.25 2    ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       0.125               Entercoccus faecalis 276                                                                      0.5  ≦0.06                                                                        ≦0.06                                                                        2    0.125                                                                               0.25 ≦0.06                                                                        0.125                                                                               ≦0.06                                                                       0.25                Entercoccus gallinarum 245                                                                    64   8    ≦0.06                                                                        2    0.5  2    1    1    0.5 4                   Haemophilus influenzae RD                                                                     >64  >64  >64  32   >64  32   32   >64  32  >64                 Escherichia coli EC14                                                                         >64  >64  >64  >64  >64  >64  >64  >64  >64 >64                 Streptococcus pyogenes C203                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        Streptococcus pneumoniae P1                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06        __________________________________________________________________________     Organism       226  227  228  229  230  231  232  233  234 235                 __________________________________________________________________________     Staphylococcus aureus 446                                                                     1    2    4    1    0.25 0.25 4    4    4   0.5                 Staphylococcus aureus 489                                                                     0.5  2    2    1    0.25 ≦0.06                                                                        8    4    4   0.5                 Staphylococcus aureus 447                                                                     0.5  2    4    2    0.5  0.25 16   16   8   0.25                Staphylococcus aureus X400                                                                    0.25 1    1    1    0.5  ≦0.06                                                                        8    8    8   0.125               Staphylococcus aureus X778                                                                    0.25 4    4    1    0.25 ≦0.06                                                                        8    8    4   0.5                 Staphylococcus aureus 491                                                                     0.25 2    1    0.5  0.125                                                                               ≦0.06                                                                        4    8    8   0.125               Staphylococcus aureus S13E                                                                    0.5  4    8    1    0.5  ≦0.06                                                                        8    8    8   0.125               Staphylococcus aureus SA1199                                                                  1    4    4    1    0.25 ≦0.06                                                                        16   32   8   0.25                Staphylococcus aureus SA1199A                                                                 0.125                                                                               0.6  ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        2    4    2   ≦0.06        Staphylococcus aureus SA1199B                                                                 1    4    4    1    0.25 ≦0.06                                                                        32   16   8   0.5                 Staphylococcus haemolyticus 105                                                               2    2    2    1    1    ≦0.06                                                                        2    >64  8   0.5                 Staphylococcus haemolyticus 415                                                               1    4    4    2    2    0.5  32   >64  16  1                   Staphylococcus epidermidis 270                                                                1    2    2    0.5  0.5  0.125                                                                               8    8    4   0.5                 Entercoccus faecium 180                                                                       ≦0.06                                                                        0.25 1    ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.5  2    1   0.5                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        1    2    1   ≦0.06        Entercoccus faecalis 2041                                                                     ≦0.06                                                                        0.25 0.25 ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        2         0.5 ≦0.06        Entercoccus faecalis 276                                                                      0.25 0.5  1    0.25 ≦0.06                                                                        ≦0.06                                                                        8    8    4   0.125               Entercoccus gallinarum 245                                                                    1    4    4    2    2    0.5  32   >64  16  1                   Haemophilus influenzae RD                                                                     32   >64  >64  2    32   32   16   >64  >64 8                   Escherichia coli EC14                                                                         >64  >64  >64  >64  >64  >64  >64  >64  >64 >64                 Streptococcus pyogenes C203                                                                   ≦0.06                                                                        ≦0.06                                                                        0.125                                                                               ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06  ≦0.06        Streptococcus pneumoniae P1                                                                   ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        ≦0.06                                                                        0.5  0.25                                                                               ≦0.06        __________________________________________________________________________                            Organism       236 237 238 239 240 241                  __________________________________________________________________________                            Staphylococcus aureus 446                                                                     1   2   1   1   1   0.5                                         Staphylococcus aureus 489                                                                     4   0.5 0.5 0.5 1   0.5                                         Staphylococcus aureus 447                                                                     4   1   0.5 0.5 0.5 1                                           Staphylococcus aureus X400                                                                    2   1   1   0.25                                                                               0.25                                                                               0.5                                         Staphylococcus aureus X778                                                                    2   0.5 0.5 0.25                                                                               0.5 1                                           Staphylococcus aureus 491                                                                     4   0.25                                                                               0.25                                                                               0.25                                                                               0.25                                                                               0.25                                        Staphylococcus aureus S13E                                                                    4   0.25                                                                               0.125                                                                              0.5 0.5 0.25                                        Staphylococcus aureus SA1199                                                                  4   1   0.5 0.5 0.5 1                                           Staphylococcus aureus SA1199A                                                                 2   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                Staphylococcus aureus SA1199B                                                                 4   0.25                                                                               0.5 0.5 0.25                                                                               1                                           Staphylococcus haemolyticus 105                                                               4   1   0.5 1   1   1                                           Staphylococcus haemolyticus 415                                                               4   1   2   1   2   1                                           Staphylococcus epidermidis 270                                                                2   0.5 0.5 0.25                                                                               0.25                                                                               0.5                                         Entercoccus faecium 180                                                                       1   0.25                                                                               0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                Entercoccus faecium 180-1                                                                     1   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                Entercoccus faecalis 2041                                                                     1   0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                Entercoccus faecalis 276                                                                      2   1   ≦0.06                                                                       0.25                                                                               0.5 ≦0.06                                Entercoccus gallinarum 245                                                                    4   1   ≦0.06                                                                       1   2   ≦0.06                                Haemophilus influenzae RD                                                                     32  8   >64 >64 >64 >64                                         Escherichia coli EC14                                                                         >64 >64 >64 >64 >64 >64                                         Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                               ≦0.06                                Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06         __________________________________________________________________________

The formula I compounds have also shown in vivo antimicrobial activity against experimentally-induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with the test organism, the activity observed was measured as an ED₅₀ value (effective dose in mg/kg to protect 50% of the test animals: see W. Wick et al., J. Bacteriol. 81, 233-235 (1961)). ED₅₀ values observed for illustrative compounds are given in Table 4.

                  TABLE 4                                                          ______________________________________                                         In Vivo Activity of Formula I Compounds ED50                                   (mg/kg/2)                                                                               Stapylococcus                                                                              Streptococcus                                                                              Streptococcus                                 Compound aureus      pyogenes    pneumoniae                                    ______________________________________                                         vancomycin                                                                              1.2         0.8         1.1                                           A82846A  0.19        0.084       0.39                                          A82846B  0.25        0.12        0.18                                          A82846C  1.3         1.5         4.6                                            1       0.086       0.052       0.025                                          2       0.27        0.014       0.025                                          4       0.36        0.012       0.036                                          5       0.13        0.039       0.036                                          6       0.15        0.013       0.021                                          8       0.12        >0.5        0.273                                          12      0.13        >0.5        >0.5                                           14      0.43        0.37        >0.5                                           22      0.049       >0.5        >.05                                           25      0.16        0.087       0.088                                          29      0.088       0.1         0.054                                          32      0.055       0.034       0.039                                          36      0.19        0.28        0.31                                           39      0.1         0.045       <0.031                                         41      n.d.        0.082       0.087                                          46      n.d.        0.378       0.156                                          49      0.053       0.045       <0.031                                         50      0.1         0.047       0.057                                          51      0.16        0.057       0.036                                          52      0.052       0.046       0.074                                          53      0.077       0.16        0.071                                          57      0.041       0.054       0.046                                          64      n.d.        0.044       <0.031                                         87      n.d.        0.054       0.027                                          90      n.d.        0.058       0.049                                          93      n.d.        0.074       0.012                                          94      n.d.        0.16        0.049                                          97      n.d.        0.066       0.038                                         100      n.d.        0.062       0.046                                         104      n.d.        0.12        0.041                                         105      n.d.        0.12        0.041                                         106      n.d.        0.2         0.036                                         107      n.d.        0.27        0.092                                         108      n.d.        0.046       0.041                                         111      n.d.        0.099       0.084                                         114      n.d.        0.091       0.76                                          116      n.d.        0.89        0.058                                         118      n.d.        0.91        0.046                                         119      n.d.        0.16        0.08                                          120      n.d.        0.058       0.005                                         121      n.d.        0.041       0.047                                         122      n.d.        0.23        0.31                                          123      n.d.        0.076       0.039                                         124      n.d.        0.092       0.041                                         131      n.d.        <0.031      0.077                                         204      n.d.        <0.031      0.046                                         211      n.d.        <0.031      0.041                                         223      n.d.        <0.031      <0.031                                        229      n.d.        0.058       0.078                                         230      n.d.        0.046       0.078                                         ______________________________________                                          n.d. = not done                                                          

One important aspect of the antimicrobial activity of many of the formula I compounds is their activity against vancomycin- resistant enterococci. This activity is illustrated in Table 5, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant and vancomycin-susceptibie enterococci (Enterococcus faecium and Enterococcus faecalis, mean geometric MIC (mcg/mL)), as determined using the standard broth micro-dilution assay. End points were read after 24-hour incubation. Modification of the amino sugar of the disaccharide moiety provides improved activity against vancomycin-resistant strains over the parent glycopeptide antibiotic.

                  TABLE 5                                                          ______________________________________                                                        Vancomycin                                                                               Vancomycin                                            Compound       Resistant Sensitive                                             No.            Strains   Strains                                               ______________________________________                                         vancomycin     282       3.9                                                   A82846A        >64       1.7                                                   A82846B        29        0.22                                                  A828460        353       1.3                                                   1              0.25      0.0061                                                2              0.044     0.00038                                               3              2.8       0.11                                                  4              0.50      0.062                                                 5              0.50      0.072                                                 6              1.2       0.14                                                  7              2.8       0.43                                                  8              1.0       0.57                                                  9              11        0.38                                                  10             3.4       3.5                                                   11             6.7       0.22                                                  12             1.7       1.1                                                   13             19        0.76                                                  14             0.50      0.76                                                  15             6.7       0.14                                                  16             9.5       0.67                                                  17             9.5       0.38                                                  18             6.7       0.38                                                  19             4.8       0.22                                                  20             4.8       0.38                                                  21             5.7       4.3                                                   22             1.0       1.5                                                   23             5.7       2.0                                                   24             54        0.67                                                  25             4.0       0.22                                                  26             54        0.66                                                  27             45        1.5                                                   28             4.7       0.71                                                  29             0.21      0.031                                                 30             4.7       0.071                                                 31             9.5       1.2                                                   32             0.50      0.089                                                 33             2.8       0.18                                                  34             4.0       3.4                                                   35             5.6       0.25                                                  36             0.25      0.21                                                  37             2.4       0.25                                                  38             4.0       0.42                                                  39             1.2       0.09                                                  40             0.50      0.31                                                  41             0.84      0.21                                                  42             1.7       0.089                                                 43             13        1.1                                                   44             13        0.50                                                  45             2.0       0.50                                                  46             0.71      0.50                                                  47             4.7       0.57                                                  48             4.8       0.50                                                  49             0.71      0.083                                                 50             0.12      0.054                                                 51             0.84      0.22                                                  52             0.59      0.11                                                  53             0.35      0.25                                                  54             1.7       0.56                                                  55             13        1.7                                                   56             19        1.0                                                   57             0.35      0.041                                                 58             5.7       0.76                                                  59             51        0.42                                                  60             19        3.0                                                   61             16        0.65                                                  62             9.5       0.22                                                  63             54        0.66                                                  64             0.71      0.077                                                 65             2.4       0.20                                                  66             16        0.76                                                  67             1.7       0.16                                                  68             6.7       0.25                                                  69             13        0.44                                                  70             2.0       0.092                                                 71             11        0.57                                                  72             4.7       0.28                                                  73             11        0.25                                                  74             11        0.33                                                  75             16        0.50                                                  76             8.0       0.29                                                  78             16        0.76                                                  79             0.84      0.042                                                 80             1.7       0.25                                                  81             1.0       0.042                                                 82             22        0.50                                                  83             54        1.7                                                   84             23        0.66                                                  85             3.4       0.11                                                  86             1.4       0.036                                                 87             0.71      0.047                                                 88             1.7       0.055                                                 89             11        0.44                                                  90             0.71      0.041                                                 91             2.8       0.11                                                  92             1.7       0.082                                                 93             0.42      0.042                                                 94             0.50      0.041                                                 95             1.7       0.054                                                 96             1.4       0.11                                                  97             0.71      0.054                                                 98             2.4       0.095                                                 99             72        0.76                                                  100            0.71      0.042                                                 101            4.0       0.25                                                  102            2.0       0.13                                                  103            4.0       0.33                                                  104            1.2       0.062                                                 105            0.84      0.062                                                 106            0.71      0.034                                                 107            0.59      0.082                                                 108            0.84      0.04                                                  109            72        0.22                                                  110            1.7       0.047                                                 111            0.71      0.031                                                 112            1.4       0.072                                                 111            0.84      0.054                                                 114            0.59      0.031                                                 115            8.0       0.19                                                  116            0.42      0.031                                                 117            4.8       0.14                                                  118            0.84      0.048                                                 119            0.59      0.048                                                 120            1.0       0.072                                                 121            1.0       0.063                                                 122            1.0       0.054                                                 123            1.0       0.041                                                 124            0.84      0.047                                                 125            3.4       0.14                                                  126            2.4       0.11                                                  127            1.2       0.33                                                  128            2.0       0.11                                                  129            27        1.52                                                  130            4.8       0.22                                                  131            0.84      0.028                                                 132            1.2       0.048                                                 133            4.0       0.13                                                  134            2.0       0.13                                                  135            4.8       0.22                                                  136            23        0.76                                                  137            6.7       0.38                                                  138            38        0.87                                                  139            23        0.38                                                  140            6.7       0.19                                                  141            8.0       0.25                                                  142            45        1.5                                                   143            2.0       0.048                                                 144            11        9.2                                                   145            64        1.3                                                   146            64        1.5                                                   147            25        1.3                                                   148            0.15      0.052                                                 149            45        0.66                                                  150            1.7       0.25                                                  151            4.5       0.14                                                  152            27        1.2                                                   153            1.4       0.083                                                 154            2.8       0.072                                                 155            128       1.3                                                   156            5.7       0.17                                                  157            2.0       0.054                                                 158            1.7       1.0                                                   159            27        0.50                                                  160            9.5       0.22                                                  161            23        0.44                                                  162            4.8       0.12                                                  163            2.0       0.87                                                  164            1.7       0.11                                                  165            4.0       0.062                                                 166            1.7       0.055                                                 167            1.0       0.055                                                 168            3.4       0.10                                                  169            19        0.50                                                  170            8.0       0.22                                                  171            9.5       0.22                                                  172            3.4       0.13                                                  173            2.0       0.12                                                  174            19        0.76                                                  175            9.5       0.22                                                  176            1.2       0.13                                                  178            2.8       0.13                                                  179            1.7       0.060                                                 180            >128      0.71                                                  181            8.0       0.060                                                 182            13        0.250                                                 183            23        0.130                                                 184            27        0.570                                                 185            4.7       0.060                                                 186            11        0.290                                                 189            2.4       0.10                                                  190            6.7       0.29                                                  191            6.7       0.57                                                  192            0.84      0.035                                                 193            2         0.072                                                 194            2.4       0.083                                                 195            2.0       0.042                                                 196            1.7       0.027                                                 197            1.2       0.16                                                  198            3.4       0.062                                                 199            1.4       0.036                                                 200            1.4       0.041                                                 201            1.2       0.44                                                  202            1.4       0.76                                                  203            1.0       0.036                                                 204            0.71      0.031                                                 205            1         0.036                                                 206            1.7       0.095                                                 207            1.2       0.50                                                  208            2.8       0.17                                                  209            1.2       0.136                                                 210            0.84      0.041                                                 211            0.35      0.024                                                 212            0.50      0.036                                                 213            1.0       0.55                                                  214            0.71      0.024                                                 215            2.8       0.25                                                  216            0.35      0.032                                                 217            13        0.57                                                  218            1.0       0.11                                                  219            0.71      0.044                                                 220            0.71      0.05                                                  221            0.71      0.041                                                 222            0.84      0.072                                                 223            0.79      0.055                                                 224            0.63      0.055                                                 225            0.63      0.072                                                 226            1.6       0.041                                                 227            0.71      0.11                                                  228            1.0       0.14                                                  229            0.50      0.024                                                 230            0.35      0.031                                                 231            1.7       0.11                                                  232            0.71      0.29                                                  233            1.7       1.7                                                   234            2         2                                                     235            2.4       0.25                                                  236            1.4       0.5                                                   237            1.0       0.048                                                 238            1.4       0.14                                                  239            2.8       0.095                                                 240            1.19      0.055                                                 241            1.4       0.048                                                 ______________________________________                                    

A number of the lactic acid bacteria including all Leuconostocs, all Pediococci, and some Lactobacilli, are intrinsically resistant to vancomycin. With the increased use of vancomycin, infections due to these bacteria have been reported with increasing frequency in immunocompromised patients (Handwerger et I., Reviews of Infectious Disease 12:602-610 (1990); Ruoff e: al., Journal of Clinical Microbiology 26:2064-2068 (1988)). One important aspect of the antimicrobial activity of the formula I compounds is their activity against the vancomycin-resistant lactic acid bacteria. The compounds of the present are useful in inhibiting the growth of vancomycin-resistant lactic bacteria such as Leuconostoc, Pedicocci, and Lactobacilli and thus, controlling opportunistic infections by this group of bacteria. This activity is illustrated in Table 6, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant lactic acid bacteria (Pedicoccus acidilacti Pedicoccus pentosaceus, Leuconostoc lactis, Leuconostoc mesenteroides, Leuconostoc pseudomesenteroides, Leuconostoc citreum, and Lactobacillus confusus, mean geometric MIC (mcg/mL)), as determined using a standard agar dilution assay on brain-heart infusion agar.

                                      TABLE 6                                      __________________________________________________________________________     In Vitro Activity of Formula I Compounds MIC (mcg/ml)/Compound                 Pedioccccus Pediococcus                                                                          Leuconostoc                                                                          Leuconostoc                                                                           Leuconostoc                                     acidilacti  pentosaceus                                                                          lactis                                                                               mesenteroides                                                                         pseudomesent-                                                                         Leuconostoc                                                                          Lactobacillus                      (mean of 10)                                                                               (mean of 2)                                                                          (mean of 2)                                                                          (mean of 4)                                                                           eroides                                                                               citreum                                                                              confusus                           __________________________________________________________________________     Vancomycin                                                                           891   1024  1024  1024   >1024  >1024 1024                               A82846B                                                                              141   >256  64    >256   >256   >256  >256                                1    18    23    23    64     >128   >128  64                                  2    5.9   11    4.0   16     32     64    16                                  4    7.5   16    16    16     32     128   32                                  5    2.8   8.0   8.0   8      16     64    16                                  6    4.3   8.0   8.0   9.5    16     64    16                                 14    3.7   5.7   8.0   11     32     64    32                                 29    4.0   8.0   5.7   6.7    16     32     8                                 32    12.1  16    16    16     32     64    16                                 36    9.2   16    16    16     32     32    32                                 39    26    32    32    32     64     >64   32                                 41    71    91    91    91     >128   >128  64                                 49    55    64    64    64     128    128   64                                 50    51    64    64    64     128    128   64                                 51    87    91    64    76     >128   >128  64                                 52    55    64    64    76     64     >128  64                                 58    55    64    64    64     128    128   64                                 108   12    23    8.0   10     32     64    16                                 118   16    16    11    13     32     64    16                                 122   24    16    16    16     32     64    16                                 124   20    16    16    16     64     64    16                                 __________________________________________________________________________

Pharmaceutical formulations of the formula I compounds are also part of this invention. Thus, the compound, preferably in the form of a pharmaceutically acceptable salt, can be formulated for oral or parenteral administration for the 5 therapeutic or prophylactic treatment of bacterial infections.

For example, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. The compositions comprising a formula I compound will contain from about 0.1 to about 90% by weight of the active compound, and more generally from about 10 to about 30%. The compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid.

Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used.

It may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.

For intravenous (IV) use, a water soluble form of the antibiotic can be dissolved in one of the commonly used intravenous fluids and administered by infusion. Such fluids as, for example, physiological saline, Ringer's solution, or 5% dextrose solution can be used.

For intramuscular preparations, a sterile formulation of a suitable soluble salt form of the compound, for example the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as pyrogen-free water (distilled), physiological saline or 5% glucose solution. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, for example, an ester of a long chain fatty acid such as ethyl oleate.

For oral use, a sterile formulation of a suitable salt form of the antibiotic, for example, the hydrochloride salt, formulated in a diluent such as distilled or deionized water, is particularly useful.

Alternatively, the unit dosage form of the antibiotic can be a solution of the antibiotic, preferably in its salt form, in a suitable diluent in sterile, hermetically sealed ampoules. The concentration of the antibiotic in the unit dosage may vary, for example, from about 1 percent to about 50 percent depending on the particular form of the antibiotic and its solubility and the dose desired by the physician.

In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive microorganisms, in animals. The compounds of this invention are particularly useful in treating infections caused by methicillin-resistant staphylococci. Also, the compounds are useful in treating infection due to enterococci. Examples of such diseases are severe staphylococcal infections, for example, staphylococcal endocarditis and staphylococcal septicemia. The animal may be either susceptible to, or infected with, the microorganism. The method comprises administering to the animal an amount of a formula I compound which is effective for this purpose. In general, an effective amount of a formula I compound is a dose between about 0.5 and about 100 mg/kg. A preferred dose is from about 1 to about 60 mg/kg of active compound. A typical daily dose for an adult human is from about 50 mg to about 5 g.

In practicing this method, the antibiotic can be administered in a single daily dose or in multiple doses per day. The treatment regimen may require administration over extended periods of time, for example, for several days or for from one to six weeks. The amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the antibiotic and the microorganism or microorganisms involved in the infection.

A convenient method of practicing the treatment method is to administer the antibiotic via intravenous infusion. In this procedure a sterile formulation of a suitable soluble salt of the antibiotic is incorporated in a physiological fluid, such as 5% dextrose solution, and the resulting solution is infused slowly IV. Alternatively, the piggy-back method of IV infusion can also be used.

In order to illustrate more fully the preparation of this invention, the following examples are provided, but are not to be construed as a limitation on the scope of the invention.

EXAMPLE 1 Method A

Preparation of Compound 2

A mixture of A82846B-triacetate, (2.25 g, 1.27 mmol, 1.0 equivalents (eq)) in 1:1 DMF/methanol (140 mL) under an atmosphere of argon was treated with 4-biphenylcarboxaldehyde (331 mg, 2.12 mmol, 1.7 eq). The resulting mixture was heated to 70° C. and maintained as such for 1.75-2 hours. The solution was then treated with sodium cyanoborohydride (554 mg, 8.83 mmol, 6.9 eq). Heating at 70° C. was continued for an additional 1.75-2 hours after which the reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (150 mL), and lyophilized to give a solid. The solid was purified by preparative reverse-phase high performance liquid chromatography (HPLC) using a Waters 3 x (40 x 100 mm) C18 Nova-Pak cartridge with Waters C18 Nova-pak guard insert and utilizing TEAP buffer system. The analytical method for analysis was: 0.2% TEA/phosphoric acid (TEAP), pH=3, the gradient system at time 0 was 5% CH₃ CN/94.8% H₂ O with 0.2% TEAP held constant and at 20 minutes was 60% CH₃ CN/39.8% H₂ O with 0.2% TEAP held constant. The UV wavelength used was 235 nm and the flow rate was 2 ml/minute. Analysis was done using a Waters Nova-pak C18 RCM column (8×100mm) with a Nova-pak C18 guard insert. It s necessary to desalt the product after reverse phase purification when this HPLC method is used.

Desalting was accomplished by adding the purified product to 5-10 ml of H₂ O. 1 N HC1 was added dropwise with stirring to dissolve the sample. The pH at this point was approximately 1-3. The pH of the solution was then raised to 8.2 with 1 N NaOH. A white solid precipitated out of solution. The mixture was cooled, filtered, and dried under vacuum at room temperature for 8-15 hours to give the zwitter ion (or neutral compound) of the desired product, compound 2 (p-phenylbenzyl•A82846B), (1.02 g, 45%).

EXAMPLE 2

Preparation of Compound 4

A mixture of A82846B-triacetate (1.5 g, 0.848 mmol, 1.0 eq) in methanol (100 mL) under an atmosphere of argon was treated with p-phenoxybenzaldehyde (298 mg, 1.51 mmol, 1.8 eq). The resulting mixture was heated to reflux and maintained as such for 2 hours. The solution was then treated with sodium cyanoborohydride (326 mg, 5.18 mmol, 6.1 eq). Heating at reflux was continued for an additional 2 hours after which the reaction mixture was cooled to room temperature and evaporated to dryness in vacuo.

The product was purified by reverse-phase HPLC with a TFA buffer. The analytical method for analysis was accomplished by using a Waters Nova-pak C18 RCM column (8 ×100 mm) with a Nova-pak C18 guard insert, eluting with a 2.0 ml/minute linear gradient of 15% acetonitrile/0.1% TFA at time zero to 80% acetonitrile/0.1% TFA at 15 minutes. The fractions containing the products were detected by ultraviolet scan at 235 nm. The organic solvent of the desired fractions was removed and the mixture was lyophilized to a white solid to give 0.618 mg of p-phenoxybenzyl•A82846B compound 4-tris(trifluroacetate) salt (20% yield). No desalting or further purification was necessary. This method is also especially useful in the preparation of Compound 2 wherein phenylbenzaldehyde is one of the starting materials.

EXAMPLE 3 Method B

Preparation of Compound 176

A mixture of A82846B-triacetate (280 mg, 0.157 mmol, 1.0 eq) in 1:1 DMF/methanol (30 mL) was treated with 8-phenyloctanal (59 mg, 0.29 mmol, 1.8 eq) and sodium cyanoborohydride (60 mg, 0.95 mmol, 6.1 eq). The resulting mixture was heated, under an atmosphere of nitrogen, to 70° C. and maintained as such for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give a residue. Purification of the product was accomplished by reverse-phase preparative HPLC utilizing a Waters 2 ×(40 ×100 mm) C18 Nova-Pak cartridge with Waters C18 Nova-Pak guard insert. Elution was accomplished with a 30 minute linear gradient (time=0 minutes 95% TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid)/5% CH₃ CN to t=30 minutes 20% TEAP/80% CH₃ CN) with a flow rate of 40 mL/minute and UV detection at 280 nm. The desired fraction was concentrated in vacuo then desalted with a Waters Sep-Pak cartridge as described below. This afforded compound 176 in 22% yield (60 mg).

The resulting compound was desalted as follows. A Waters Sep-Pak cartridge was pre-wet with methanol (2-3 column volumes) then conditioned with water (2-3 column volumes). The sample, dissolved in a minimum volume of water, was loaded onto the Sep- Pak column which was then washed with water (2-3 column volumes) to remove the unwanted salts. The product was then eluted with an appropriate solvent system, typically 1:1 CH₃ CN/H₂ O, CH₃ CN, and/or methanol. The organic solvent component was removed in vacuo and the resulting aqueous solution lyophilized to give the final product.

EXAMPLE 4

Preparation of Compound 229

A three liter 3-necked flask was fitted with a condenser, nitrogen inlet and overhead mechanical stirring apparatus. The flask was charged with pulverized A82846B acetate salt (20.0 g, 1.21×10⁻³ mol) and methanol (1000 mL) under a nitrogen atmosphere. 4'-chlorobiphenylcarboxaldehyde (2.88 g, 1.33×10⁻ ² mol, 1.1 eq.) was added to this stirred mixture, followed by methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g, 1.33×10⁻² mol, 1.1 eq.) was added followed by methanol (500 mL). The resulting mixture was heated to reflux (about 65° C).

After 1 hour at reflux, the reaction mixture attained homogeneity. After 25 hours at reflux, the heat source was removed and the clear reaction mixture was measured with a pH meter (6.97 at 58.0° C.) 1 N NaOH (22.8 mL) was added dropwise to adjust the pH to 9.0 (at 54.7° C.). The flask was equipped with a distillation head and the mixture was concentrated under partial vacuum to a weight of 322.3 grams while maintaining the pot temperature between 40°-45° C.

The distillation head was replaced with an addition funnel containing 500 mL of isopropanol (IPA). The IPA was added dropwise to the room temperature solution over 1 hour. After approximately 1/3 of the IPA was added, a granular precipitate formed. The remaining IPA was added at a faster rate after precipitation had commenced. The flask was weighed and found to hold 714.4 grams of the IPA/methanol slurry.

The flask was re-equipped with a still-head and distilled under partial vacuum to remove the remaining methanol. The resulting slurry (377.8 g) was allowed to chill in the freezer overnight. The crude product was filtered through a polypropylene pad and rinsed twice with 25 mL of cold IPA. After pulling dry on the funnel for 5 minutes, the material was placed in the vacuum oven to dry at 40° C. A light pink solid (22.87 g (theory =22.43 g)) was recovered. HPLC analysis versus a standard indicated 68.0% weight percent of Compound 229 (4- 4-chlorophenyl!benzyl-A82846B! in the crude solid, which translated into a corrected crude yield of 69.3%.

The products of the reaction were analyzed by reverse-phase HPLC utilizing a Zorbax SB-C18 column with ultraviolet light (UV; 230 nm) detection. A 20 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minutes to 40% aqueous buffer/60% CH₃ CN at time=20 minutes was used, where the aqueous buffer was TEAP (5 ml CH₃ CN, 3 ml phosphoric acid in 1000 ml water).

EXAMPLE 5

Table 7 summarizes the preparation and certain physical characteristics of the exemplified compounds. The yield of the product was calculated using the amount of the formula II compound as the limiting reagent. The following terms are found in Table 6 and are defined here. "Method" refers to the method of synthesis as described in Examples 1 and 2, or 3. "Reagent Equivalents" refers to the molar equivalents of the aldehyde and reducing agent relative to the formula II compound. "FAB-MS (M+3H)" refers to Fast atom bombardment-mass spectrometry.

                  TABLE 7                                                          ______________________________________                                                                     Reagent                                                                        Equivalents                                        Compound Yield   Method/    (aldehyde/                                                                              FAB-MS                                    No.      (%)     DMF:MeOH   NaBH3CN) (M + 3H)                                  ______________________________________                                         1        28      A/1:1      1.7/6.9  1733*                                     2        45      A/1:1      1.7/6.9  1760                                      3        28      A/1:1      1.8/7.6  1732**                                    4        20      A/0:1      1.8/6.1  1776***                                   5        30      A/0:1      1.8/6.1  1790                                      6        10      A/0:1      1.8/6.1  1768***                                   7        55      A/0:1      1.8/6.1  1740***                                   8        1       A/0:1      1.8/6.1  1826                                      9        3       A/0:1      1.8/6.1  1764***                                   10       6       A/0:1      1.8/6.1  1868                                      11       8       A/0:1      1.8/6.1  1784                                      12       46      A/0:1      1.8/6.1  1940                                      13       32      A/0:1      1.8/6.1  1783**                                    14       5.4     A/1:1      1.9/4.2  1859                                      15       42      A/0:1      1.8/6.1  1763                                      16       39      A/0:1      1.8/6.1  1807**                                    17       41      A/0:1      1.8/6.1  1798                                      18       27      A/0:1      1.8/6.1  1817                                      19       30      A/0:1      1.8/6.1  1739                                      20       5       A/1:1      1.8/1.8  1775*                                     21       11      A/1:1      1.8/1.8  1872*                                     22       8       A/1:1      1.8/1.8  1829**                                    23       ND      A/0:1      1.8/3.6  1888***                                   24       34      A/0:1      1.7/2.5  1685                                      25       31      A/0:1      1.8/1.6  1779                                      26       30      A/0:1      1.7/2.5  1685                                      27       19      A/0:1      1.8/2.5  1734**                                    28       35      A/0:1      1.6/1.6  1735                                      29       39      A/0:1      1.6/1.6  1785**                                    30       29      A/0:1      1.6/1.6  1734**                                    31       11      A/0:1      1.7/2.5  1684**                                    32       28      A/0:1      1.5/1.6  1771**                                    33       ND      A/1:1      1.8/1.8  1789                                      34       ND      A/1:1      1.8/1.8  1836                                      35       ND      A/1:1      1.8/1.8  1785                                      36       ND      A/0:1      1.8/1.8  1835                                      37       31      A/0:1      1.5/1.5  1752***                                   38       16      A/0:1      1.5/1.6  1709                                      39       46      A/0:1      1.5/1.5  1773                                      40       29      A/1:1      1.8/1.8  1846*                                     41       46      A/0:1      1.5/1.5  1729                                      42       53      A/0:1      1.5/1.5  1780                                      43       22      A/0:1      1.1/1.5  1799***                                   44       42      A/0:1      1.5/1.5  1749                                      45       50      A/0:1      1.1/1.5  1841                                      46       38      A/0:1      1.1/1.5  1850                                      47       40      A/0:1      1.5/1.5  1687                                      49       44      A/0:1      1.5/1.5  1776***                                   48       22      A/0:1      1.5/1.5  1728***                                   50       32       A/1:10    2.0/1.5  1774                                      51       32      A/0:1      1.5/1.5  1820                                      52       31      A/0:1      1.5/1.5  1819**                                    53       43      A/0:1      1.5/1.5  1896                                      54       4       A/1:1      1.8/1.8  1789                                      55       21      A/0:1      1.5/1.5  1767                                      56       20      A/0:1      1.1/1.5  1741                                      57       29      A/0:1      1.5/1.5  1820**                                    58       22      A/0:1      1.5/1.5  1727                                      59       ND      A/1:1      1.8/1.8  1803                                      60       33      A/0:1      1.1/1.5  1777**                                    61       24      A/0:1      1.1/1.5  1723                                      62       ND      A/1:1      1.8/1.8  1789**                                    63       ND      A/1:1      1.8/1.8  1789**                                    64       30      A/0:1      1.5/1.5  1805                                      65       24      A/0:1      1.1/1.5  1763                                      66       17      A/0:1      1.1/1.5  1704***                                   67       22      A/0:1      1.1/1.5  1766***                                   68       ND      A/1:1      1.8/1.8  1802                                      69       ND      A/1:1      1.8/1.8  1803                                      70       44      A/0:1      1.1/1.5  1821                                      71       4       A/0:1      1.1/1.5  1796***                                   72       32      A/0:1      1.5/1.5  1750***                                   73       ND      A/1:1      1.8/1.8  1753                                      74       17      A/0:1      1.1/1.5  1815                                      75       23      A/0:1      1.5/1.5  1806***                                   76       16      A/1:1      1.8/1.8  1711                                      77       ND      A/1:1      1.8/1.8  1742                                      78       5       A/1:1      1.8/1.8  1728                                      79       ND      A/1:1      1.8/1.8  1783**                                    80       46      A/0:1      1.5/1.5  1843****                                  81       52      A/0:1      1.5/1.5  1844***                                   82       29      A/0:1      1.5/1.5  1726***                                   83       7       A/0:1      1.5/1.5  1798**                                    84       8       A/0:1      1.5/1.5  1700                                      85       30      A/0:1      1.5/1.5  1775                                      86       45      A/0:1      1.5/1.5  1809                                      87       42      A/0:1      1.1/1.5  1854**                                    88       36      A/0:1      1.1/1.5  1854**                                    89       43      A/1:1      1.8/1.8  1711                                      90       13      A/1:1      1.8/1.8  1787                                      91       20       A/1:10    1.511.5  1759**                                    92       23       A/1:10    1.5/1.5  1777                                      93       42      A/0:1      1.5/1.5  1823                                      94       41      A/0:1      1.1/1.5  1854**                                    95       49      A/0:1      1.1/1.5  1789**                                    96       34      A/0:1      1.1/1.5  1832                                      97       42       A/1:10    1.5/1.5  1773**                                    98       31      A/0:1        1/1.5  1805                                      99       ND      A/1:1      1.8/1.8  1770**                                    100      ND      A/1:1      1.8/1.8  1787                                      101      34      A/1:1      1.19/1.8 1761                                      102      41      A/0:1      1.5/1.5  1805                                      103      37      A/0:1        1/1.5  1788***                                   104      34      A/0:1      1.1/1.5  1819**                                    105      ND      A/1:1      1.7/2.0  1838*                                     106      ND      A/1:1      1.7/2.0  1844                                      107      ND      A/1:1      1.1/1.1  1802                                      108      ND      A/0:1      1.8/1.8  1791**                                    109      ND      A/0:1      1.8/1.8  1789                                      110      15      A/0:1      1.1/1.5  1881                                      111      ND      A/1:1      1.8/1.8  1843                                      112      16      A/1:1      1.8/1.8  1764                                      113      45      A/0:1      1.1/1.5  1805**                                    114      52      A/0:1      1.1/1.5  1888**                                    115      39      A/0:1      1.1/1.5  1791                                      116      ND      A/1:1      1.8/2.0  1834                                      117      29      A/0.1      1.5/1.7  1803**                                    118      28      A/0:1        2/1.5  1765**                                    119      41      A/0:1        1/1.5  1843                                      120      38      A/0:1      1.1/1.5  1757                                      121      41      A/0:1      1.1/1.5  1799                                      122      24      A/1:1      1.8/2.6  1863                                      123      55      A/0:1      1.1/1.5  1795**                                    124      17       A/1:10      3/1.5  1781**                                    125      36      A/0:1      1.5/1.8  1841                                      126      26      A/0:1      1.6/1.8  1818                                      127      54      A/0:1      1.1/1.5  1810                                      128      34      A/0:1      1.4/1.8  1831                                      129      ND      A/1:1      1.4/1.8  1780                                      130      4       A/0:1      1.1/1.5  1795**                                    131      42      A/0:1      1.1/1.5  1834**                                    132      49      A/0:1      1.1/1.5  1843                                      133      41      A/0:1      1.1/1.5  1855                                      134      30      A/0:1      1.1/1.5  1801**                                    135      ND      A/1:1      1.8/1.8  1779                                      136      ND      A/1:1      1.8/1.8  1699                                      137      ND      A/1:1      1.8/1.8  1760                                      138      ND      A/1:1      1.8/1.8  1741                                      139      13       A/1:10    2.4/1.5  1749**                                    140      11       A/1:10    2.9/1.5  1750*                                     141      ND      A/1:1      2.3/5.3  1742                                      142      ND      A/1:1      2.5/5.4  1826                                      143      ND      A/1:1      1.8/1.8  1861                                      144      ND      A/1:1      1.5/1.5  1922                                      145      ND      A/1:1      1.1/1.1  1716                                      146      ND      A/1:1      1.35/1.8 1780*                                     147      ND      A/1:1      1.5/1.8  1769                                      148      31       A/1:10      3/1.5  1857                                      149      18      A/0:1      1.1/1.5  1777                                      150      22      A/1:1        2/4.8  1803                                      151      ND      A/1:1      1.8/1.8  1760                                      152      ND      A/1:1      1.8/1.8  1826****                                  153      22       A/1:10    2.5/1.6  1782                                      154      ND      A/1:1      1.8/1.8  1780                                      155      13      A/0:1      1.6/1.6  1768                                      156      41      A/1:9      1.2/1.6  1788                                      157      9       A/1:1      2.7/5.4  1810                                      158      ND      A/1:1      1.8/4.1  1854                                      159      13      A/1:9        1/1.6  1807                                      160      13      A/1:9      0.95/1.6 1774                                      161      ND      A/1:1      1.8/1.8  1690                                      162      ND      A/1:1      3.1/6.9  1804                                      163      ND      A/1:1      1.9/5.3  1854                                      164      ND      A/1:1      1.8/1.8  1772                                      165      21      A/1:1      2.0/4.9  1810                                      166      20      A/1:1      2.0/6.2  1870                                      167      23      A/1:1      1.8/4.1  1914                                      168      ND      A/1:1      1.8/1.8  1737                                      169      15      A/1:1      1.8/4.1  1700                                      170      39      A/0:1      1.2/1.1  1728                                      171      32      A/0:1      1.2/1.5  1729**                                    172      11      B/1:1      2.2/4.8  1755**                                    173      51      A/1:9      1.3/1.7  1909                                      174      35      A/1:9      1.5/1.6  1816                                      175      22      B/1:1      1.9/6.2  1712                                      176      21      B/1:1      1.8/6.1  1732                                      177      ND      A/1:1      3.6/1.8  1774                                      178      33      A/1:9      1.4/1.7  1788**                                    179      22      B/1:1      1.8/3.8  1748                                      180      16      A/1:1      1.1/1.3  1591***                                   181      14      A/1:1      1.1/1.3  1617                                      182      17      A/0:1      1.6/6.3  1725                                      183      17      A/0:1      1.6/6.3  1691**                                    184      8       A/0:1       1.6/6.26                                                                               1707**                                    185      21      A/1:1      1.1/3.0  1725**                                    186      8       A/1:1      1.1/3.0  1630**                                    187      16      A/1.1      1.6/3.0  2110**                                    188      6       A/1.1      1.5/5.0  2976**                                    189      20       A/1:10      1/1.2  1747**                                    190      9        A/1:10    1.5/1.5  1716                                      191      18      B/1:1      1.8/4.1  1771**                                    192      11      A/0:1      ND/1.8   1738                                      193      24       A/1:10    2.0/1.5  1820**                                    194      27       A/1:10    2.0/1.5  1821                                      195      18      B/1:1      1.6/3.6  1798                                      196      18      B/1:1      1.8/3.9  1754                                      197      35      B/1:1      1.5/3.5  1810                                      198      14      B/1:1      1.5/3.7  1784                                      199      ND      B/1:1      1.5/2.8  1772                                      200      11      B/1:1      1.5/3.7  1828                                      201      14      B/1:1      1.8/6.3  1873**                                    202      7       B/1:1      1.3/5.9  1889**                                    203      15      A/0:1      1.1/1.1  1843                                      204      16      B/1:1      2.0/5.6  1746                                      205      23      B/1:1      1.8/3.7  1732                                      206      11      A/0:1      1.1/1.1  1777                                      207      11      B/1:1      1.6/4.2  1813**                                    208      26      B/1:1      1.9/3.9  1703                                      209      20      A/1:1      1.0/1.6  1774                                      210      35      A/0:1      1.0/1.0  1788                                      211      26      A/0:1      1.3/1.8  1777                                      212      48      A/1:1      1.1/3.1  1849**                                    213      56      A/1:1      1.0/3.6  1849**                                    214      9       B/1:1      1.9/1.9  1732                                      215      35      A/0:1      1.3/1.8  1820***                                   216      31      A/0:1      1.3/1.8  1828***                                   217      12      B/1:1      2.0/2.1  1676                                      218      24       A/1:10    1.2/1.5  1766***                                   219      24      A/1:1      1.4/3.5  1860                                      220      21      A/0:1      1.3/1.8  1785                                      221      42      A/0:1      1.3/1.8  1787                                      222      20      A/0:1      1.1/1.1  1787                                      223      32      A/1:1      2 4/4.5  1817**                                    224      36      A/1:1      1.6/5.6  1773**                                    225      ND      A/0:1      1.1/1.1  1787                                      226      28      A/1:1      1.5/3.0  1766*                                     227      22      A/1:1      1.2/3.7  1777**                                    228      21      A/0:1        1/1.1  1848**                                    229      16      A/0:1        1/1.2  1793                                      230      27      A/0:1      1.3/1.8  1838***                                   231      36      A/0:1      1.3/1.8  1785*                                     232      32      A/1:1      1.8/4.6  1806                                      233      5       A/1:1      1.1/7.3  1878                                      234      7       B/1:1      1.5/3.5  1836*                                     235      15      B/1:1      1.4/4.8  1750                                      236      4       B/1:1      1.4/6.3  1819**                                    237      14      A/0:1      1.1/1.1  1787                                      238      25      B/0:1      1.1/1.1  1771                                      239      22      B/1:1      1.6/1.5  1810                                      240      4.7      A/1:60    1.2/1.1  1810***                                   241      24      B/1:1      1.1/2.5  1779**                                    242      N.D.     A/1:50    1.1/1.2  1787                                      243      20      A/0:1      1.1/1.1  1790                                      244      24      C/0:1      1.1/1.1  1808                                      ______________________________________                                          N.D. = Not determined                                                          *M + H                                                                         **M + 2H                                                                       ***M + 4H                                                                      ****M + 6H                                                               

EXAMPLE 6

Capsule Formulation

Capsules containing 250 mg of Compound 2 are prepared using the following ingredients:

    ______________________________________                                         Ingredient         Weight                                                      ______________________________________                                         Compound 2 HCl salt                                                                               255.4 mg                                                    Corn starch flowable powder                                                                         150 mg                                                    Corn starch        144.6 mg                                                    ______________________________________                                    

Compound 2 (HCI salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 7

Capsule Formulation

Capsules containing 250 mg of Compound 229 are prepared using the following ingredients:

    ______________________________________                                         Ingredient         Weight                                                      ______________________________________                                         Compound 229 HCl salt                                                                             255.4 mg                                                    Corn starch flowable powder                                                                         150 mg                                                    Corn starch        144.6 mg                                                    ______________________________________                                    

Compound 2 (HCl salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 8

Suspension Formulation

A sterile insoluble form of compound 2 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the -it vehicle:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 9

Suspension Formulation

A sterile insoluble form of compound 229 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the following vehicle: Ingredient Weight

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 10

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 11

Tablet Formulation Tablets containing 250 mg of compound 229 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 12

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

    ______________________________________                                         Ingredient             Weight                                                  ______________________________________                                         Compound 2 HCl salt    255.4 mg                                                Microcrystalline cellulose                                                                            101.1 mg                                                Croscarmellose sodium   12.0 mg                                                Providone               12.0 mg                                                Magnesium stearate      3.0 mg                                                 Stearic acid            4.0 mg                                                 Purified water          0.16 ml                                                ______________________________________                                    

EXAMPLE 13

Tablet Formulation

Tablets containing 250 mg of compound 229 are prepared with the following composition:

    ______________________________________                                         Ingredient             Weight                                                  ______________________________________                                         Compound 229 HCl salt  255.4 mg                                                Microcrystalline cellulose                                                                            101.1 mg                                                Croscarmellose sodium   12.0 mg                                                Providone               12.0 mg                                                Magnesium stearate      3.0 mg                                                 Stearic acid            4.0 mg                                                 Purified water          0.16 ml                                                ______________________________________                                     

We claim:
 1. A compound of the formula: ##STR9## or salt thereof, wherein: R⁶ is vancosaminyl; andR⁷ is (C₁ -C₁₂ alkyl)--R₈ and is attached to the amino group of R⁶ ; R⁸ is a group of the formula: ##STR10## wherein q is 0 to 4; R¹² is independently selected from the group consisting of: (i) halo, (ii) nitro, (iii) (C₁ -C₆)alkyl, (iv) (C₁ -C₆)alkoxy, (v) halo-(C₁ -C₆)alkyl, (vi) halo-(C₁ -C₆)alkoxy, (vii) hydroxy, and (vii) (C₁ -C₆)thioalkyl; r is 1 to 5; provided that the sum of q and r is no greater than 5; Z is selected from the group consisting of:(i) a single bond, (ii) divalent (C₁ -C₆)alkyl unsubstituted or substituted with hydroxy, (C₁ -C₆)alkyl, or (C₁ -C₆)alkoxy, (iii) divalent (C₂ -C₆)alkenyl, (iv) divalent (C₂ -C₆)alkynyl, and (v) a group of the formula --(C(R¹⁴)₂)_(s) --R¹⁵ -- or --R¹⁵ -- (C(R⁴)₂)_(s) --, wherein s is 0-6; wherein each R¹⁴ substituent is independently selected from hydrogen, (C₁ -C₆)-alkyl, and (C₄ -C₁₀) cycloalkyl; and R¹⁵ is selected from --O--, --S--, --SO--, --SO₂ --, --SO₂ --O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C₁ -C₆ alkyl)-, --C(O)NH--, --NHC(O)--, and N═N; R¹³ is independently selected from the group consisting of:(i) (C₄ -C₁₀) heterocyclyl, (ii) heteroaryl, (iii) (C₄ -C₁₀) cycloalkyl unsubstituted or substituted with (C₁ -C₆) alkyl, and (iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C₁ -C₁₀) alkyl, (C₁ -C₁₀)alkoxy, halo-(C₁ -C₃)alkoxy, halo-(C₁ -C₃)alkyl, (C₁ -C₃)alkoxyphenyl, phenyl, phenyl-(C₁ -C₃) alkyl, (C₁ -C₆)alkoxyphenyl, phenyl-(C₂ -C₃)alkynyl, and (C₁ -C₃) alkylphenyl.
 2. The compound of claim 1 wherein R⁷ represents 4-phenylbenzyl, or a salt thereof.
 3. A pharmaceutical composition comprising a compound of claim 11 with one or more pharmaceutically acceptable carriers therefor.
 4. A pharmaceutical composition comprising a compound of claim 2 with one or more pharmaceutically acceptable carriers therefor.
 5. A method of treating susceptible bacterial infections which comprises administering an antibacterially effective amount of a composition of claim 3 to a host in need of such treatment.
 6. A method of treating susceptible bacterial infections which comprises administering an antibacterially effective amount of a composition of claim 4 to a host in need of such treatment.
 7. A method of claim 5 wherein the susceptible bacterial infection is caused by a vancomycin-resistant enterococcus.
 8. A method of claim 6 wherein the susceptible bacterial infection is caused by a vancomycin-resistant enterococcus.
 9. A process for making a compound of claim 1 which comprises(a) reacting a compound of the formula ##STR11## wherein R¹ is vancosaminyl with an aldehyde corresponding to R⁷ as defined in claim 1 in methanol at about 25° C. to about 100° C.; (b) continuing the reaction until formation of a Schiff's base; and (c) reducing the Schiff's base by addition of a metal borohydride to the mixture of about 25° C. to about 100° C. 